Lipoic acid synthetase (LIAS) has been demonstrated to play a crucial role in the progression of cancer. Exploring the underlying mechanisms and biological functions of LIAS could have potential therapeutic guidance for cancer treatment. Our study has explored the expression levels and prognostic values of LIAS in pan-cancer through several bioinformatics platforms, including TIMER2.0, Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2.0), and Human Protein Atlas (HPA). We found that a high LIAS expression was related to the good prognosis in patients with kidney renal clear cell carcinoma (KIRC), rectum adenocarcinoma (READ), breast cancer, and ovarian cancer. Inversely, a high LIAS expression showed unfavorable prognosis in lung cancer patients. In addition, the genetic alteration, methylation levels, and immune analysis of LIAS in pan-cancer have been evaluated. To elucidate the underlying molecular mechanism of LIAS, we conduct the single-cell sequencing to implicate that LIAS expression was related to hypoxia, angiogenesis, and DNA repair. Thus, these comprehensive pan-cancer analyses have conveyed that LIAS could be potentially significant in the progression of various cancers. Moreover, the LIAS expression could predict the efficacy of immunotherapy in cancer patients.

Solute carrier family 31 member 1 () encodes a protein that functions as a homotrimer for the uptake of dietary copper. As a vital member of the cuproptosis gene family, it plays an essential role in both normal tissues and tumors. In this study, we analyzed across human cancer types to gain a better understanding of 's role in cancer development. We searched for information using online databases to analyze, systematically and comprehensively, the role of in tumors. Amongst nine cancer types, the expression of was significantly different between tumors and normal tissues. According to further analysis, pancreatic cancer had the highest mutation rate of the gene, and the methylation levels of the gene were significantly reduced in seven tumors. The expression of is also linked to the infiltration of tumors by immune cells, the expression of immune checkpoint genes, and immunotherapy markers (TMB and MSI), suggesting that may be of particular relevance in immunotherapy. This thorough analysis of across different types of cancer gives us a clear and comprehensive insight into its role in causing cancer on a systemic level.

Nanocatalytic therapy (NCT) has made great achievements in tumor treatments due to its remarkable enzyme-like activities and high specificity. Nevertheless, the limited types of nanozymes and undesirable tumor microenvironments (TME) greatly weaken the therapeutic efficiency. Developing a combination therapy integrating NCT and other strategies is of great significance for optimal treatment outcomes. Herein, a AuPt-loaded Cu-doped polydopamine nanocomposite (AuPt@Cu-PDA) with multiple enzyme-like activities was rationally designed, which integrated photothermal therapy (PTT) and NCT. The peroxidase (POD)-like activity of AuPt@Cu-PDA can catalyze hydrogen peroxide (HO) into ·OH, and the catalase (CAT)-mimic activity can decompose HO into O to alleviate hypoxia of TME, and O can be further converted into toxic ·O by its oxidase (OXD)-mimic activity. In addition, Cu in AuPt@Cu-PDA can effectively consume GSH overexpressed in tumor cells. The boosting of reactive oxygen species (ROS) and glutathione (GSH) depletion can lead to severe oxidative stress, which can be enhanced by its excellent photothermal performance. Most importantly, the accumulation of Cu can disrupt copper homeostasis, promote the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), disrupt the mitochondrial tricarboxylic acid (TCA) cycle, and finally result in cuproptosis. Collectively, photothermal and photoacoustic imaging (PTI/PAI)-guided cuproptosis-enhanced NCT/PTT can be achieved. This work may expand the application of nanozymes in synergistic therapy and provide new insights into cuproptosis-related therapeutic strategies.

DLD is a key gene involved in "cuproptosis," but its roles in tumor progression and immunity remain unclear. Exploring the potential mechanisms and biological roles of DLD may provide new insights for therapeutic strategies for tumors. In the present study, we analyzed the role of DLD in a variety of tumors by using several bioinformatic tools. The results showed that compared with normal tissues, tumor tissues representing multiple cancers showed significant differential expression of DLD. High DLD expression was associated with a good prognosis in BRCA, KICH, and LUAD. Conversely, high expression levels of DLD were detrimental to patient prognosis in many other tumors, such as COAD, KIRC, and KIRP. In addition, the associations of DLD with infiltrating immune cells, genetic alterations and methylation levels across cancers were assessed. Aberrant expression of DLD was positively correlated with most infiltrating immune cells, especially neutrophils. The DLD methylation level was significantly decreased in COAD, LIHC, and LUSC but significantly increased in BRCA. DLD had the highest mutation rate (6.04%) in ESCA. In LUSC, patients with genetic alterations in DLD showed a poorer prognosis. At the single-cell level, the roles of DLD in regulating cancer-associated biological functions, such as metastasis, inflammation, and differentiation, were explored. Afterward, we further investigated whether several disease-associated genes could be correlated with DLD. GO enrichment analysis indicated that DLD-related genes were mainly associated with mitochondria-related cellular components, aerobic respiration and the tricarboxylic acid cycle. Finally, the correlations between DLD expression and immunomodulatory genes, immune checkpoints, and sensitivity to some antitumor drugs were investigated. It is worth noting that DLD expression was positively correlated with immune checkpoint genes and immunomodulatory genes in most cancers. In conclusion, this study comprehensively analyzed the differential expression, prognostic value and immune cell infiltration-related function of DLD across cancers. Our results suggest that DLD has great potential to serve as a candidate marker for pancancer prognosis and immunotherapy and may provide a new direction for cancer treatment development.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO and Cu in the tumor microenvironment. The exposed CaO further yields hydrogen peroxide (HO) and Ca in a weakly acidic environment to strengthen the Cu-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

A novel form of cell death, cuproptosis, was recently identified to be mediated by the binding of copper to lipoylated enzymes of the tricarboxylic acid cycle. Cuproptosis-related genes (CRGs) may play a crucial role in the progression of pancreatic adenocarcinoma (PAAD), which often exhibits metabolic reprogramming. In the present study, univariate Cox regression analysis and Kaplan-Meier survival analysis were performed to identify prognostic CRGs. Data from the Cancer Therapeutics Response Portal and the Genomics of Drug Sensitivity in Cancer database were downloaded for drug sensitivity analysis. was identified as the only prognostic CRG in PAAD (HR = 2.72; 95% CI, 1.10-6.74). Functional enrichment analyses indicated that the basic function of is closely related to metabolism, and multiple tumor-promoting and immune response-related pathways were enriched in -high PAAD samples. The influence of and related genes on cancer immunity was evaluated by comprehensive immune infiltration analyses, which revealed the value of these genes as biomarkers for evaluating the sensitivity to immunotherapy. Additionally, high expression induced drug resistance, and significantly increased resistance to commonly used chemotherapeutics in PAAD, such as gemcitabine, oxaliplatin, 5-fluorouracil, and irinotecan. In conclusion, our study preliminarily revealed the prognostic value of , which is correlated with PAAD progression, chemoresistance, and immune infiltration, providing a valuable reference for PAAD treatment. However, our findings need to be confirmed by further in vivo and in vitro experiments.

Copper (Cu) is an essential element that is involved in a variety of biochemical processes. Both deficiency and accumulation of Cu are associated with various diseases; and a high amount of accumulated Cu in cells can be fatal. The production of reactive oxygen species (ROS), oxidative stress, and cuproptosis are among the proposed mechanisms of copper toxicity at high concentrations. Elesclomol (ELC) is a mitochondrion-targeting agent discovered for the treatment of solid tumors. In this review, we summarize the synthesis of this drug, its mechanisms of action, and the current status of its applications in the treatment of various diseases such as cancer, tuberculosis, SARS-CoV-2 infection, and other copper-associated disorders. We also provide some detailed information about future directions to improve its clinical performance.

Exercise can produce a large number of cytokines that may benefit cancer patients, including Interleukin 15 (IL-15). IL-15 is a cytokine that has multiple functions in regulating the adaptive and innate immune systems and tumorigenesis of lung and breast cancers. However, the roles of IL-15 in other types of cancer remain unknown. In this article, we try to systematically analyze if IL-15 is a potential molecular biomarker for predicting patient prognosis in pan-cancer and its connection with anti-cancer effects of exercise. The expression of IL-15 was detected by The Cancer Genome Atlas (TCGA) database, Human protein Atlas (HPA), and Genotype Tissue-Expression (GTEX) database. Analysis of IL-15 genomic alterations and protein expression in human organic tissues was analyzed by the cBioPortal database and HPA. The correlations between IL-15 expression and survival outcomes, clinical features, immune-associated cell infiltration, and ferroptosis/cuproptosis were analyzed using the TCGA, ESTIMATE algorithm, and TIMER databases. Gene Set Enrichment Analysis (GSEA) was performed to evaluate the biological functions of IL-15 in pan-cancer. The differential analysis suggested that the level of IL-15 mRNA expression was significantly downregulated in 12 tumor types compared with normal tissues, which is similar to the protein expression in most cancer types. The high expression of IL-15 could predict the positive survival outcome of patients with LUAD (lung adenocarcinoma), COAD (colon adenocarcinoma), COADREAD (colon and rectum adenocarcinoma), ESCA (esophageal carcinoma), SKCM (skin cutaneous melanoma), UCS (uterine carcinosarcoma), and READ (rectum adenocarcinoma). Moreover, amplification was found to be the most frequent mutation type of IL-15 genomic. Furthermore, the expression of IL-15 was correlated to the infiltration levels of various immune-associated cells in pan-cancer assessed by the ESTIMATE algorithm and TIMER database. In addition, IL-15 is positively correlated with ferroptosis/cuproptosis-related genes (ACSL4 and LIPT1) in pan-cancer. Levels of IL-15 were reported to be elevated in humans for 10-120 min following an acute exercise. Therefore, we hypothesized that the better prognosis of pan-cancer patients with regular exercise may be achieved by regulating level of IL-15. Our results demonstrated that IL-15 is a potential molecular biomarker for predicting patient prognosis, immunoreaction, and ferroptosis/cuproptosis in pan-cancer and partly explained the anti-cancer effects of exercise.

The latest research identified cuproptosis as an entirely new mechanism of cell death. However, as a key regulator in copper-induced cell death, the prognostic and immunotherapeutic value of FDX1 in pan-cancer remains unclear. Data from the UCSC Xena, GEPIA, and CPTAC were analyzed to conduct an inquiry into the overall differential expression of FDX1 across multiple cancer types. The expression of FDX1 in GBM, LUAD and HCC cell lines as well as their control cell lines was verified by RT-QPCR. The survival prognosis, clinical features, and genetic changes of FDX1 were also evaluated. Finally, the relationship between FDX1 and immunotherapy response was further explored through Gene Set Enrichment Analysis enrichment analysis, tumor microenvironment, immune cell infiltration, immune gene co-expression and drug sensitivity analysis. The transcription and protein expression of FDX1 were significantly reduced in most cancer types and had prognostic value for the survival of certain cancer patients such as ACC, KIRC, HNSC, THCA and LGG. In some cancer types, FDX1 expression was also markedly correlated with the clinical characteristics, TMB, MSI, and antitumor drug susceptibility or resistance of different tumors. Gene set enrichment analysis showed that FDX1 was significantly associated with immune-related pathways. Moreover, the expression level of FDX1 was confirmed to be strongly correlated with immune cell infiltration, immune checkpoint genes, and immune regulatory genes to a certain extent. This study comprehensively explored the potential value of FDX1 as a prognostic and immunotherapeutic marker for pan-cancer, providing new direction and evidence for cancer therapy.

Two cationic [Cu(L)](ClO) (1, 2), and four neutral doubly bridged-phenoxido-copper(II) complexes [Cu(L)] (3, 4) and [Cu(L)(HO)]‧2HO (5, 6) as well as 1D polymeric catena-[Cu(L)] (7), where HL and HL represent tripodal tetradentate pyridyl or aliphatic-amino groups based 2,4-disubstituted phenolates, were synthesized and thoroughly characterized by various spectroscopic methods and single crystal X-ray analysis. The molecular structures of the complexes exhibited diverse geometrical environments around the central Cu(II) atoms. The in vitro antiproliferative activity of the isolated complexes and selected parent free ligands were screened against some human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, MCF-7). The most promising cytotoxicity against cancer cells were obtained for 1-6, while complex 6 was found as the best performing as compared to the reference drug cisplatin. The cytotoxicity study of complex 6 was therefore extended to wider variety of cancer cell lines (HOS, A549, PANC-1, CaCo2, HeLa) and results revealed its significant cytotoxicity on all investigated human cancer cells. The cell uptake study showed that cytotoxicity of 6 (3 μM concentration and 24 h of incubation) against A2780 cells was almost independent from the intracellular levels of copper. The effect of complexes 4, 6 and 7 on cell cycle of A2780 cells indicates that the mechanism of action in these complexes is not only different from that of cisplatin but also different among them. Complex 7 was able to induce apoptosis in A2780 cells, while complexes 4 and 6 did not and on the other hand, they showed considerable effect on autophagy induction and there are some clues that these complexes were able to induce cuproptosis in A2780 cells.

Background:Studies have shown that the expressions and working mechanisms of Dihydrolipoamide S-acetyltransferase (DLAT) in different cancers vary. It is necessary to analyze the expressions and regulatory roles of DLAT in tumors systematically. Methods:Online public-platform literature on the relationships between DLAT expression levels and tumor prognosis, methylation status, genetic alteration, drug sensitivity, and immune infiltration has been reviewed. The literature includes such documents as The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Receiver Operating Characteristic plotter (ROC plotter). The molecular mechanisms of DLAT were explored with the Gene Set Enrichment Analysis (GSEA). The relationship between down-regulated DLAT and autophagy in two liver hepatocellular carcinoma (LIHC) cell lines was confirmed with the western blot method, colony formation assay, and transmission electron microscopy. Tissue microarrays were validated through the immunohistochemical staining of DLAT. Results:DLAT is upregulated in the LIHC, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and stomach adenocarcinoma (STAD) tumors but is down-regulated in the head and neck squamous cell carcinoma (HNSC) and kidney renal clear cell carcinoma (KIRC) tumors in comparison with normal tissues. For LIHC patients treated with 5-Fluorouracil and Lenvatinib, the DLAT levels of those in the drug-resistant group are significantly high. In LIHC cells, autophagy will be inhibited, and cell death will be induced when DLAT breaks down. Moreover, there exist positive correlations between DLAT expression levels and infiltration of B cells, DC cells, Tregs, and CD8+ T cells in kidney chromophobe (KICH), breast invasive carcinoma (BRCA), prostate adenocarcinoma (PRAD), LIHC and HPV+ HNSC. In LIHC, markers of Tregs are positively correlated with DLAT. Compared with those of normal tissues, the staining intensity of DLAT and the amount of Tregs marker CD49d in LIHC increase. Conclusions:Through this study, the expressions of DLAT in various cancer types can be understood comprehensively. It suggests that DLAT may be a prognostic marker for LIHC, LUAD, LUSC, STAD and KIRC. A high DLAT expression in LIHC may promote tumorigenesis by stimulating autophagy and inhibiting anti-tumor immunity.

BACKGROUND:Disulfidptosis is independent of apoptosis, ferroptosis, and cuproptosis and is associated with cancer progression, treatment response, and prognosis. However, the predictive potential of disulfidptosis-associated lncRNAs in colon adenocarcinoma (COAD) and their features in the tumor immune microenvironment (TIME) require further elucidation. METHODS:RNA transcriptome, clinical information, and mutation data of COAD samples were obtained from the TCGA database. The risk model was first constructed by co-expression analysis of disulfidptosis genes and lncRNAs, and prognostic lncRNAs were screened using Cox regression, followed by least absolute shrinkage and selection operator analysis. Enrichment analyses were performed to explore the underlying biological functions and signaling of model-associated differentially expressed genes (MADEGs). Moreover, TIME of MADEGs was analyzed to assess the immunotherapy. Finally, the expression levels of the lncRNAs were verified by taking specimens of patients with COAD from the Affiliated Hospital of Qingdao University. RESULTS:We constructed a prognosis-related risk model based on four disulfidptosis-associated lncRNAs (ZEB1-AS1, SNHG16, SATB2-AS1, and ALMS1-IT1). By analyzing the survival of patients in the whole, training, and test groups, we found that patients with COAD in the low-risk group had better overall survival than those in the high-risk group. Validation of the model via Cox analysis and clinical indicators demonstrated that the model had a decent potential for predicting the prognosis of patients with COAD. Enrichment analyses revealed that the MADEGs were related to disulfidptosis-associated biological functions and cancer pathways. Furthermore, patients with COAD in the high-risk group had more positive responses to immune checkpoint inhibitors (ICIs) than those in the low-risk group, as confirmed by TIME analysis. ZEB1-AS1, SNHG16, and ALMS1-IT1 were expressed at higher levels in tumor samples than those in the corresponding paracancerous samples (p < 0.05), whereas SATB2-AS1 was upregulated in the paracancerous samples (p < 0.05). CONCLUSIONS:This signature may guide prognosis, molecular mechanisms, and treatment strategies, including ICIs and chemotherapy, in patients with COAD.

Immunotherapy has attracted widespread attention in cancer treatment and has achieved considerable success in the clinical treatment of some tumors, but it has a low response rate in most tumors. To achieve sufficient activation of the immune response, significant efforts using nanotechnology have been made to enhance cancer immune response. In recent years, the induction of various regulated cell death (RCD) has emerged as a potential antitumor immuno-strategy, including processes related to apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and cuproptosis. In particular, damage-associated molecular patterns (DAMPs) released from the damaged membrane of dying cells act as in situ adjuvants to trigger antigen-specific immune responses by the exposure of an increased antigenicity. Thus, RCD-based immunotherapy offers a new approach for enhancing cancer treatment efficacy. Furthermore, incorporation with multimodal auxiliary therapies in cell death-based immunotherapy can trigger stronger immune responses, resulting in more efficient therapeutic outcome. This review discusses different RCD modalities and summarizes recent nanotechnology-mediated RCDs in cancer immunotherapy.

BACKGROUND:Diabetic kidney disease (DKD) is the most lethal complication of diabetes. Diverse programmed cell death (PCD) has emerged as a crucial disease phenotype that has the potential to serve as an indicator of renal function decline and can be used as a target for researching drugs for DKD. METHODS:Microarray-based transcriptome profiling and single-nucleus transcriptome sequencing (snRNA-seq) related to DKD were retrieved from the Gene Expression Omnibus (GEO) database. 13 PCD-related genes (including alkaliptosis, apoptosis, autophagy-dependent cell death, cuproptosis, disulfidptosis, entotic cell death, ferroptosis, lysosome-dependent cell death, necroptosis, netotic cell death, oxeiptosis, parthanatos, and pyroptosis) were obtained from various public databases and reviews. The gene set variation analysis (GSVA) analysis was used to explore the pathway activity of these 13 PCDs in DKD, and the pathway activity of these PCDs in different renal cells was studied based on DKD-related snRNA-seq data. To identify the core PCDs that play a significant role in DKD, we analyzed the relationships between different types of PCD and immune infiltration, fibrosis-related gene expression levels, glomerular filtration rate (GFR), and diagnostic efficiency in DKD. Using the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm, we screened for core death genes among the core PCDs and constructed a cell death-related signature (CDS) risk score based on the Least Absolute Shrinkage and Selection Operator (LASSO). Finally, we validated the predictive performance of the CDS risk score in an independent validation set. RESULTS:We identified 4 core PCD pathways, namely entotic cell death, apoptosis, necroptosis, and pyroptosis in DKD, and further applied the WGCNA algorithm to screen 4 core death genes (CASP1, CYBB, PLA2G4A, and CTSS) and constructed a CDS risk score based on these genes. The CDS risk score demonstrated high diagnostic efficiency for DKD patients, and those with higher scores had higher levels of immune cell infiltration and poorer GFR. CONCLUSION:Our study sheds light on the fact that multiple PCDs contribute to the progression of DKD, highlighting potential therapeutic targets for treating this disease.

Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment. ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.

Mitochondria accumulate copper in their matrix for the eventual maturation of the cuproenzymes cytochrome c oxidase and superoxide dismutase. Transport into the matrix is achieved by mitochondrial carrier family (MCF) proteins. The major copper transporting MCF described to date in yeast is Pic2, which imports the metal ion into the matrix. Pic2 is one of ~30 MCFs that move numerous metabolites, nucleotides and co-factors across the inner membrane for use in the matrix. Genetic and biochemical experiments showed that Pic2 is required for cytochrome c oxidase activity under copper stress, and that it is capable of transporting ionic and complexed forms of copper. The Pic2 ortholog SLC25A3, one of 53 mammalian MCFs, functions as both a copper and a phosphate transporter. Depletion of SLC25A3 results in decreased accumulation of copper in the matrix, a cytochrome c oxidase defect and a modulation of cytosolic superoxide dismutase abundance. The regulatory roles for copper and cuproproteins resident to the mitochondrion continue to expand beyond the organelle. Mitochondrial copper chaperones have been linked to the modulation of cellular copper uptake and export and the facilitation of inter-organ communication. Recently, a role for matrix copper has also been proposed in a novel cell death pathway termed cuproptosis. This review will detail our understanding of the maturation of mitochondrial copper enzymes, the roles of mitochondrial signals in regulating cellular copper content, the proposed mechanisms of copper transport into the organelle and explore the evolutionary origins of copper homeostasis pathways.

Photodynamic therapy (PDT) represents a non-invasive treatment strategy currently utilized in the clinical management of selected cancers and infections. This technique is predicated on the administration of a photosensitizer (PS) and subsequent irradiation with light of specific wavelengths, thereby generating reactive oxygen species (ROS) within targeted cells. The cellular effects of PDT are dependent on both the localization of the PS and the severity of ROS challenge, potentially leading to the stimulation of various cell death modalities. For many years, the concept of regulated cell death (RCD) triggered by photodynamic reactions predominantly encompassed apoptosis, necrosis, and autophagy. However, in recent decades, further explorations have unveiled additional cell death modalities, such as necroptosis, ferroptosis, cuproptosis, pyroptosis, parthanatos, and immunogenic cell death (ICD), which helps to achieve tumor cell elimination. Recently, nanoparticles (NPs) have demonstrated substantial advantages over traditional PSs and become important components of PDT, due to their improved physicochemical properties, such as enhanced solubility and superior specificity for targeted cells. This review aims to summarize recent advancements in the applications of different metal-based NPs as PSs or delivery systems for optimized PDT in cancer treatment. Furthermore, it mechanistically highlights the contribution of RCD pathways during PDT with metal NPs and how these forms of cell death can improve specific PDT regimens in cancer therapy.

Due to the urgent demand for more anti-cancer methods, the new applications of metal ions in cancer have attracted increasing attention. Especially the three kinds of the new mode of cell death, including ferroptosis, calcicoptosis, and cuproptosis, are of great concern. Meanwhile, many metal ions have been found to induce cell death through different approaches, such as interfering with osmotic pressure, triggering biocatalysis, activating immune pathways, and generating the prooxidant effect. Therefore, varieties of new strategies based on the above approaches have been studied and applied for anti-cancer applications. Moreover, many contrast agents based on metal ions have gradually become the core components of the bioimaging technologies, such as MRI, CT, and fluorescence imaging, which exhibit guiding significance for cancer diagnosis. Besides, the new nano-theranostic platforms based on metal ions have experimentally shown efficient response to endogenous and exogenous stimuli, which realizes simultaneous cancer therapy and diagnosis through a more controlled nano-system. However, most metal-based agents have still been in the early stages, and controlled clinical trials are necessary to confirm or not the current expectations. This article will focus on these new explorations based on metal ions, hoping to provide some theoretical support for more anti-cancer ideas.

Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted.

Colorectal cancer (CRC), a tumor of the digestive system, is characterized by high malignancy and poor prognosis. Currently, targeted therapy of CRC is far away from satisfying. The molecular mechanisms of regulated cell death (RCD) have been clearly elucidated, which can be intervened by drug or genetic modification. Numerous studies have provided substantial evidence linking these mechanisms to the progression and treatment of CRC. The RCD includes apoptosis, autophagy-dependent cell death (ADCD), ferroptosis, necroptosis, and pyroptosis, and immunogenic cell death, etc, which provide potential targets for anti-cancer treatment. For the last several years, small-molecule compounds targeting RCD have been a well concerned therapeutic strategy for CRC. This present review aims to describe the function of small-molecule compounds in the targeted therapy of CRC via targeting apoptosis, ADCD, ferroptosis, necroptosis, immunogenic dell death and pyroptosis, and their mechanisms. In addition, we prospect the application of newly discovered cuproptosis and disulfidptosis in CRC. Our review may provide references for the targeted therapy of CRC using small-molecule compounds targeting RCD, including the potential targets and candidate compounds.

Cell death is a natural biological process that occurs in living organisms. Since 1963, extensive research has shed light on the occurrence, progress, and final outcome of cell death. According to different cell phenotypes, it is classified into different types, including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and so on. However, regardless of the form of cell death, what we ultimately expect is the disappearance of abnormal cells, such as tumor cells, while normal cells survive. As a result, it is vital to investigate the details of cell death, including death triggers, potent regulators, and executioners. Although significant progress has been made in understanding molecular pathways of cell death, many aspects remain unclear because of the complex regulatory networks in cells. Among them, the phosphoinositide-3-kinase (PI3K)/protein kinase B(AKT) pathway is discovered to be a crucial regulator of the cell death process. AKT, as a proto-oncogene, has become a major focus of attention in the medical community due to its role in regulating a multiplicity of cellular functions counting metabolism, immunity, proliferation, survival, transcription, and protein synthesis. Here, we explored the connection between the PI3K/AKT pathway and cell death, aiming to enhance our comprehension of the mechanism underlying this process. Such knowledge may pave the way for the subsequent development of more effective disease treatments, such as finding suitable targets for drug intervention.

The tumor microenvironment (TME) has a redox state that differs greatly from normal tissues, as characterized by the overexpression of HO and glutathione (GSH). To address the GSH-related restrictions on chemodynamic therapy (CDT) efficacy, we have developed a Cu(II)-based CDT strategy. In this study, a novel organic-inorganic hybrid drug delivery system (LDH/HA/5-FU) was conceived and prepared by the intercalation of 5-FU into the interlayer of copper-aluminum layered double hydroxide (CuAl-LDH) via ion exchange strategy and the adsorption of hyaluronic acid (HA) on the surface of CuAl-LDH. Taking advantage of the pH-degradable property of CuAl-LDH and the CD44-targeting property of HA, the formed LDH/HA/5-FU nanosheets could specifically target tumor cells' overexpressing CD44 receptor, rapidly release Cu(II) and 5-FU in tumor cells, inducing tumor cell apoptosis and cuproptosis, and long-term intracellular GSH depletion and toxic hydroxyl radicals (·OH) generation could be achieved through the cyclic catalytic reaction of Cu(I)/Cu(II). Meanwhile, peritumoral injection of LDH/HA/5-FU nanosheets might function as an adjuvant to increase the levels of antitumor tumor-associated macrophages (TAMs) and T cells. In vivo experiments further verified that the intelligently designed LDH/HA/5-FU nanosheets successfully promoted the immune systems, with an excellent inhibition efficacy towards tumors by combining Cu-based CDT and chemotherapy, showing promising potential for solid tumor treatments.

Metallomodulation cell death strategies are extensively investigated for antitumor therapy, such as cuproptosis, ferroptosis, and chemodynamic therapy (CDT). Undoubtedly, the accurate and specific elevation of metal ions levels in cancer cells is key to boosting their therapeutic index. Herein, a programmably controllable delivery system based on croconium dye (Croc)-ferrous ion (Fe ) nanoprobes (CFNPs) is developed for multiscale dynamic imaging guided photothermal primed CDT. The Croc, with kinds of electron-rich iron-chelating groups, can form the Croc-Fe complex with a precise stoichiometry of 1:1 to steadily maintain the valence state of Fe . The CFNPs can achieve pH-responsive visualization and accurate Fe release in cancerous tissues under the coactivation of "dual-key" stimulation of "acidity and near-infrared (NIR) light". The acidic tumor microenvironment actuates NIR fluorescence/photoacoustic imaging and photothermal properties of CFNPs. Sequentially, under exogenous NIR light, the CFNPs enable in vivo accurate visualization of Croc-Fe complex delivery for photothermal primed Fe release, thus achieving CDT of tumors. By leveraging multiscale dynamic imaging technologies, the complicated spatiotemporal release of Fe is sketched in a programmably controllable manner, and the domino effect of tumor pH level, photothermal effect, and CDT is also revealed, endowing customized feedback of the therapeutic panorama within the disease microenvironment.

Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases.

One new alkaloid, (S)-2-acetamido-4-(2-(methylamino)phenyl)-4-oxobutanoic acid (1), was isolated from the deep-sea-derived Penicillium citrinum XIA-16, together with 25 known compounds including ten polyketones (2-11), eight alkaloids (12-19), six steroids (20-25), and a fatty acid (26). Their planar and relative structures were determined by an analysis of 1D and 2D nuclear magnetic resonance (NMR) as well as high resolution electrospray ionization mass spectroscopy (HR-ESI-MS) data. The absolute configuration of 1 was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Penicitrinol B (6) significantly inhibited RSL3-induced ferroptosis (EC =2.0 μM) by reducing lipid peroxidation and heme oxygenase 1 (HMOX1) expression. Under the concentration of 10 μM, penicitrinol A (7) was able to inhibit cuproptosis with the cell viabilities of 68.2 % compared to the negative control (copper and elesclomol) with the cell viabilities of 14.8 %.

Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of ferredoxins as electron donors enables them to participate in many metabolic processes including steroid, heme, vitamin D, and Fe-S cluster biosynthesis in different organisms. However, the unique natural function(s) of each of the two human ferredoxins (FDX1 and FDX2) are still poorly characterized. We recently reported that FDX1 is both a crucial regulator of copper ionophore-induced cell death and serves as an upstream regulator of cellular protein lipoylation, a mitochondrial lipid-based post-translational modification naturally occurring on four mitochondrial enzymes that are crucial for TCA cycle function. Here we show that FDX1 directly regulates protein lipoylation by binding the lipoyl synthase (LIAS) enzyme promoting its functional binding to the lipoyl carrier protein GCSH and not through indirect regulation of cellular Fe-S cluster biosynthesis. Metabolite profiling revealed that the predominant cellular metabolic outcome of FDX1 loss of function is manifested through the regulation of the four lipoylation-dependent enzymes ultimately resulting in loss of cellular respiration and sensitivity to mild glucose starvation. Transcriptional profiling established that FDX1 loss-of-function results in the induction of both compensatory metabolism-related genes and the integrated stress response, consistent with our findings that FDX1 loss-of-function is conditionally lethal. Together, our findings establish that FDX1 directly engages with LIAS, promoting its role in cellular protein lipoylation, a process essential in maintaining cell viability under low glucose conditions.

Cancer is the second cause of death worldwide. Copperoptosis is a new mode of regulated cell death and is strongly associated with metabolic pathways. FDX1 is a key gene that promotes copperoptosis, and its impact on tumor pathogenesis and tumor immune response is indistinct and needs further exploration. Data was mined from the Cancer Genome Atlas database, the Broad Institute Cancer Cell Line Encyclopedia database, and the International Cancer Genome Consortium. Survival analyses included the Kaplan-Meier method for calculating the cumulative incidence of survival events and the log-rank method for comparing survival curves between groups. Immune cell infiltration levels were calculated using the Spearman correlation test and correlated with FDX1 expression to assess significance. More correlation analyses between FDX1 expression and mutational markers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), were also examined Spearman assay to explore the relation between FDX1 expression and the sensitivity of common antitumor drugs. FDX1 expression was downregulated in most kinds of cancers, and this high expression indicated better overall survival and death-specific survival. For several cancer types, FDX1 expression had a positive correlation with immune cell infiltration, and FDX1 also had a positive correlation with TMB and MSI in some cancer types, linking its expression to the assessment of possible treatment responses. The correlations between FDX1 expression and cancer in varioustissues, including clear links to cancer survival and prognosis, make FDX1 aninteresting biomarker and potential therapeutic target for cancer surveillance and futureresearch.

As a redox-sensitive protein, high-mobility group box 1 (HMGB1) is implicated in regulating stress responses to oxidative damage and cell death, which are closely related to the pathology of inflammatory diseases, including cancer. HMGB1 is a nonhistone nuclear protein that acts as a deoxyribonucleic acid chaperone to control chromosomal structure and function. HMGB1 can also be released into the extracellular space and function as a damage-associated molecular pattern protein during cell death, including during apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, alkaliptosis, and cuproptosis. Once released, HMGB1 binds to membrane receptors to shape immune and metabolic responses. In addition to subcellular localization, the function and activity of HMGB1 also depend on its redox state and protein posttranslational modifications. Abnormal HMGB1 plays a dual role in tumorigenesis and anticancer therapy ( chemotherapy, radiation therapy, and immunotherapy) depending on the tumor types and stages. A comprehensive understanding of the role of HMGB1 in cellular redox homeostasis is important for deciphering normal cellular functions and pathological manifestations. In this review, we discuss compartmental-defined roles of HMGB1 in regulating cell death and cancer. Understanding these advances may help us develop potential HMGB1-targeting drugs or approaches to treat oxidative stress-related diseases or pathological conditions. Further studies are required to dissect the mechanism by which HMGB1 maintains redox homeostasis under different stress conditions. A multidisciplinary effort is also required to evaluate the potential applications of precisely targeting the HMGB1 pathway in human health and disease. 39, 569-590.

Recent studies have proposed that pyruvate dehydrogenase E1 component subunit alpha (PDHA1), a cuproptosis-key gene, is crucial to the glucose metabolism reprogram of tumor cells. However, the functional roles and regulated mechanisms of PDHA1 in multiple cancers are largely unknown. The Cancer Genome Atlas (TCGA), GEPIA2, and cBioPortal databases were utilized to elucidate the function of PDHA1 in 33 tumor types. We found that PDHA1 was aberrantly expressed in most cancer types. Lung adenocarcinoma (LUAD) patients with high PDHA1 levels were significantly correlated with poor prognosis of overall survival (OS) and first progression (FP). Kidney renal clear cell carcinoma (KIRC) patients with low PDHA1 levels displayed poor OS and disease-free survival (DFS). However, for stomach adenocarcinoma (STAD), the downregulated PDHA1 expression predicted a good prognosis in patients. Moreover, we evaluated the mutation diversity of PDHA1 in cancers and their association with prognosis. We also analyzed the protein phosphorylation and DNA methylation of PDHA1 in various tumors. The PDHA1 expression was negatively correlated with tumor-infiltrating immune cells, such as myeloid dendritic cells (DCs), B cells, and T cells in pan-cancers. Mechanically, we used single-cell sequencing to discover that the PDHA1 expression had a close link with several cancer-associated signaling pathways, such as DNA damage, cell invasion, and angiogenesis. At last, we conducted a co-expressed enrichment analysis and showed that aberrantly expressed PDHA1 participated in the regulation of mitochondrial signaling pathways, including oxidative phosphorylation, cellular respiration, and electron transfer activity. In summary, PDHA1 could be a prognostic and immune-associated biomarker in multiple cancers.

Programmed cell death (PCD) plays an important role in many aspects of individual development, maintenance of body homeostasis and pathological processes. Ferroptosis is a novel form of PCD characterized by the accumulation of iron-dependent lipid peroxides resulting in lethal cell damage. It contributes to tumor progression in an apoptosis-independent manner. In recent years, an increasing number of non-coding RNAs (ncRNAs) have been demonstrated to mediate the biological process of ferroptosis, hence impacting carcinogenesis, progression, drug resistance, and prognosis. However, the clear regulatory mechanism for this phenomenon remains poorly understood. Moreover, ferroptosis does not usually exist independently. Its interaction with PCD, like apoptosis, necroptosis, autophagy, pyroptosis, and cuproptosis, to destroy cells appears to exist. Furthermore, ncRNA seems to be involved. Here, we review the mechanisms by which ferroptosis occurs, dissect its relationship with other forms of death, summarize the key regulatory roles played by ncRNAs, raise relevant questions and predict possible barriers to its application in the clinic, offering new ideas for targeted tumour therapy.

Lipoyltransferase 2 (LIPT2) acts as a key enzyme involved in fatty acid metabolism and cell membrane synthesis. However, the biological function of LIPT2 in various cancer types and its potential significance in prognosis continue to be unresolved. For this analysis, we evaluated the expression levels and the significance of prognosis of LIPT2 gene in all cancers by various bioinformatics methods. The results found that LIPT2 was dramatically overexpressed in the vast majority of cancers. The upregulated LIPT2 was related to bad prognosis in Brain Lower Grade Glioma (LGG), Glioma (GBMLGG), Glioblastoma multiforme (GBM), Kidney Chromophobe (KICH), and High-Risk Wilms Tumor (WT), while it had a favorable prognosis in Kidney renal clear cell carcinoma (KIRC), and Ovarian serous cystadenocarcinoma (OV), Pan-kidney cohort (KIPAN). Furthermore, we assessed the mutation status, methylation levels, and immune status of LIPT2 in pan-cancer. Single-cell sequencing results revealed the correlation of LIPT2 expression with various biological characteristics such as DNA lesion, tumor angiogenesis, cell apoptosis, metastasis, and invasion. Enrichment analysis unveiled potential molecular regulatory mechanisms. In conclusion, our research reveals a detailed key role of LIPT2 in the progression, prognosis, and immune efficacy of various forms of cancer. Therefore, we have reason to believe that LIPT2 has the potential to be a candidate biomarker for tumors.

BACKGROUND:ATP7B is a copper-transporting protein that contributes to the chemo-resistance of human cancer cells. It remains unclear what the molecular mechanisms behind ATP7B are in cancer, as well as its role in human pan-cancer studies. METHODS:Our study evaluated the differential expression of ATP7B in cancer and paracancerous tissues based on RNA sequencing data from the GTEx and TCGA. Kaplan-Meier and Cox proportional hazards regressions were used to estimate prognostic factors associated with ATP7B.The correlations between the expression of ATP7B and immune cell infiltration, tumor mutation burden, microsatellite instability and immune checkpoint molecules were analyzed. Co-expression networks and mutations in ATP7B were analyzed using the web tools. An analysis of ATP7B expression difference on drug sensitivity on tumor cells was performed using the CTRP, GDSC and CMap database. RESULTS:ATP7B expression differed significantly between cancerous and paracancerous tissues. The abnormal expression of ATP7B was linked to prognosis in LGG and KIRC. Infiltration of immune cells, tumor mutation burden, microsatellite instability and immunomodulators had all been linked to certain types of cancer. Cancer cells exhibited a correlation between ATP7B expression and drug sensitivity. CONCLUSION:ATP7B might be an immunotherapeutic and prognostic biomarker based on its involvement in cancer occurrence and development.

Ischemic stroke is one of the main causes of mortality and disability worldwide. However, the majority of patients are currently unable to benefit from intravenous thrombolysis or intravascular mechanical thrombectomy due to the limited treatment windows and serious complications. Silent mating type information regulation 2 homolog 1 (Sirt1), a nicotine adenine dinucleotide-dependent enzyme, has emerged as a potential therapeutic target for ischemic stroke due to its ability to maintain brain homeostasis and possess neuroprotective properties in a variety of pathological conditions for the central nervous system. Animal and clinical studies have shown that activation of Sirt1 can lessen neurological deficits and reduce the infarcted volume, offering promise for the treatment of ischemic stroke. In this review, we summarized the direct evidence and related mechanisms of Sirt1 providing neuroprotection against cerebral ischemic stroke. Firstly, we introduced the protein structure, catalytic mechanism and specific location of Sirt1 in the central nervous system. Secondly, we list the activators and inhibitors of Sirt1, which are primarily divided into three categories: natural, synthetic and physiological. Finally, we reviewed the neuroprotective effects of Sirt1 in ischemic stroke and discussed the specific mechanisms, including reducing neurological deficits by inhibiting various programmed cell death such as pyroptosis, necroptosis, ferroptosis, and cuproptosis in the acute phase, as well as enhancing neurological repair by promoting angiogenesis and neurogenesis in the later stage. Our review aims to contribute to a deeper understanding of the critical role of Sirt1 in cerebral ischemic stroke and to offer novel therapeutic strategies for this condition.

Inducing cancer cell death has always been a research hotspot in life sciences. With the continuous deepening and diversification of related research, the potential value of metal elements in inducing cell death has been explored. Taking iron as an example, ferroptosis, mainly characterized by increasing iron load and driving the production of large amounts of lipid peroxides and eventually leading to cell death, has recently attracted great interest in the cancer research community. After iron, copper, a trace element, has received extensive attention in cell death, especially in inducing tumor cell death. Copper and its complexes can induce autophagy or apoptosis in tumor cells through a variety of different mechanisms of action (activation of stress pathways, arrest of cell cycle, inhibition of angiogenesis, cuproptosis, and paraptosis), which are promising in cancer therapy and have become new hotspots in cancer treatment research. This article reviews the main mechanisms and potential applications of novel copper and copper compound-induced cell death, focusing on copper compounds and their anticancer applications.

Cuproptosis, a novel copper ion-dependent cell death type being regulated in cells, has raised concerns but lacks scientific analysis. Therefore, this study aimed to analyze the global status and emerging trends in cuprotosis research using bibliometric methods. Publications related to cuprotosis were systematically retrieved from the Web of Science Core Collection and then screened according to the inclusion criteria. Next, CiteSpace and Microsoft Excel 2021 were used to measure and visualize annual publications, categories, journals, countries, institutions, authors, co-cited references, and keywords to identify future global status and trends. A total of 2776 publications on cuprotosis were included, and the overall trend in the number of publications exhibited a rapid increase over the years. Biochemistry and Molecular Biology is the most common category, whereas the Journal of Inorganic Biochemistry is the most active. The United States is the country that produces the most articles, and University of Melbourne in Australia is the core institution involved in this field. Furthermore, Chan Pak of Stanford University is the most prolific author. Oxidative stress and antioxidant, the toxicity of copper in vitro, anticancer mechanism, and brain injury in neurological diseases are hot topics. The research frontiers are copper complexes, anticancer activity, DeoxyriboNucleic Acid binding, inflammation, and nanoparticles. This study provides the current status and trends in cuprotosis research. It may help researchers to identify hot topics and get ideas for future research directions in this field, focusing on copper complexes, anticancer activity, DeoxyriboNucleic Acid binding, inflammation, and nanoparticles.

Copper ions can bind directly to lipoylated components of the tricarboxylic acid (TCA) cycle, triggering the aggregation of mitochondrial lipoylated proteins and the destabilization of Fe-S cluster proteins, resulting in copper-dependent cell death. Dihydrolipoamide dehydrogenase (DLD) is a key protein of the TCA cycle and constitutes the E3 component of the α-ketoglutarate dehydrogenase complex, which is deeply interconnected with the mitochondrial electron transfer chain in the TCA cycle. Tumor cells demonstrate dependency on glutaminolysis fuelling to carry out the TCA cycle and essential biosynthetic processes supporting tumor growth. Therefore, DLD plays an important role in the tumor biological process. However, to the best of our knowledge, no pan-cancer analysis is currently available for DLD. Therefore, the present study first explored the DLD expression profile in 33 tumors in publicly available datasets, including TIMER2, GEPIA2, UALCAN, cBioPortal and STRING. TIMER2, GEPIA2 and UALCAN were used for exploring gene expression; survival prognosis was detected by GEPIA2; genetic alteration was analysed by cBioPortal; immune infiltration data was obtained from TIMER2; interacting proteins of DLD were detected by STRING. DLD was found to be highly expressed in colon, liver, lung, stomach, renal, corpus uteri endometrial and ovarian cancers compared with normal tissues, and its high expression was associated with poorer prognosis in ovarian cancer. To the best of our knowledge, the present study provided the first comprehensive pan-cancer analysis of the oncogenic role of DLD across different tumors types. As the expression of DLD in ovarian cancer was high, and high expression is associated with poor prognosis, experimental verification of DLD in ovarian cancer was conducted. In the present study, DLD expression was found to be high in the ovarian cancer OC3 cell line, compared with the normal ovarian epithelial IOSE80 cell line by reverse transcription-quantitative PCR analysis. After knockdown of DLD expression, it was found that DLD regulated metabolic pathways by suppressing the intracellular NAD/NADH ratio, which then in turn suppressed tumor cell proliferation detected by MTT assay. In conclusion, the present pan-cancer analysis of DLD demonstrated that DLD expression was associated with the clinical prognosis, immune infiltration and tumor mutational burden in 33 tumor types, and experimental verification in ovarian cancer was conducted. These results may contribute to the understanding of the role of DLD in tumorigenesis.

Due to their complexity and variability, tumors need to be treated with multimodal combined therapy, which requires the development of therapeutic agents that can provide multimodal therapeutic effects. Herein, CuMoO nanodots smaller than 10 nm that can be prepared by simple hydrothermal method are reported. These nanodots can be well dispersed in water and have good biosafety and biodegradability. Further studies show that these nanodots also present multienzyme activities, such as catalase, peroxidase and glutathione peroxidase. In addition, CuMoO nanodots exhibit high photothermal conversion efficiency (41%) under 1064 nm near-infrared laser irradiation. In vitro and in vivo experimental results indicate that CuMoO nanodots can effectively inhibit the instinctive regulation of tumor cells to oxidative stress, provide sustained treatment to achieve photothermal synergistic ferroptosis, and trigger immune responses to immunogenic cell death. It is worth mentioning that the CuMoO nanodots also cause cuproptosis of tumor cells. This study provides a promising nanoplatform for multimodal combined therapy of cancer.

SIGNIFICANCE:As a redox-sensitive protein, high-mobility group box 1 (HMGB1) is implicated in regulating stress responses to oxidative damage and cell death, which are closely related to the pathology of inflammatory diseases, including cancer. RECENT ADVANCES:HMGB1 is a non-histone nuclear protein that acts as a DNA chaperone to control chromosomal structure and function. HMGB1 can also be released into the extracellular space and function as a damage-associated molecular pattern protein during cell death, including during apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, alkaliptosis, and cuproptosis. Once released, HMGB1 binds to membrane receptors to shape immune and metabolic responses. In addition to subcellular localization, the function and activity of HMGB1 also depends on its redox state and protein posttranslational modifications. Abnormal HMGB1 plays a dual role in tumorigenesis and anticancer therapy (e.g., chemotherapy, radiation therapy, and immunotherapy) depending on tumor types and stages. CRITICAL ISSUES:A comprehensive understanding of the role of HMGB1 in cellular redox homeostasis is important for deciphering normal cellular functions and pathological manifestations. In this review, we discuss compartmental-defined roles of HMGB1 in regulating cell death and cancer. Understanding these advances may help us develop potential HMGB1-targeting drugs or approaches to treat oxidative stress-related diseases or pathological conditions. FUTURE DIRECTIONS:Further studies are required to dissect the mechanism by which HMGB1 maintains redox homeostasis under different stress conditions. A multidisciplinary effort is also required to evaluate the potential applications of precisely targeting the HMGB1 pathway in human health and disease.

Cell death is critical for the development and homeostasis of almost all multicellular organisms. Moreover, its dysregulation leads to diverse disease states. Historically, apoptosis was thought to be the major regulated cell death pathway, whereas necrosis was considered to be an unregulated form of cell death. However, research in recent decades has uncovered several forms of regulated necrosis that are implicated in degenerative diseases, inflammatory conditions and cancer. The growing insight into these regulated, non-apoptotic cell death pathways has opened new avenues for therapeutic targeting. Here, we describe the regulatory pathways of necroptosis, pyroptosis, parthanatos, ferroptosis, cuproptosis, lysozincrosis and disulfidptosis. We discuss small-molecule inhibitors of the pathways and prospects for future drug discovery. Together, the complex mechanisms governing these pathways offer strategies to develop therapeutics that control non-apoptotic cell death.

The significantly increased copper level in tumor tissues and serum indicates the close association of copper ions with tumor development, making copper ions attractive targets in the development of novel tumor treatment methods. The advanced nanotechnology developed in the past decades provides great potential for tumor therapy, among which Cu-based nanotherapeutic systems have received greater attention. Herein, the multifaceted roles of copper ions in cancer progression are summarized and the recent advances in the copper-based nanostructures or nanomedicines for different kinds of tumor therapies including copper depletion therapy, copper-based cytotoxins, copper-ion-based chemodynamic therapy and its combination with other treatments, and copper-ion-induced ferroptosis and cuproptosis activation are discussed. Furthermore, the perspectives for the further development of copper-ion-based nanomedicines for tumor therapy and clinic translation are presented by the authors.

Ferroptosis is different from other forms of cell death, such as apoptosis, autophagy, pyroptosis, and cuproptosis, mainly involving iron metabolism and lipid peroxidation. Ferroptosis plays an important role in various disease, such as malignant tumors, neuron-degenerative diseases, and cardiovascular diseases, and has become the focus of current research. Both iron overload and lipid peroxide accumulation contribute to the occurrence, development, and treatment of musculoskeletal diseases, such as osteoporosis, osteoarthritis, osteosarcoma, intervertebral disc degeneration, and spinal cord injury. For a better understanding of the potential roles ferroptosis may play in pathophysiology and treatment of common musculoskeletal disorders, this article briefly reviewed the relationship and possible mechanisms. Through an investigation of ferroptosis' role in musculoskeletal diseases' occurrence, development, and treatment, ferroptosis could offer new opportunities for clinical diagnosis and treatment.

Diabetic wounds are characterized by delayed and incomplete healing. As one of the most common complications of diabetes, diabetic wounds can be fatal in some cases. Programmed cell death (PCD) is an active and ordered cell death mode determined by genes, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis. It is currently believed that PCD plays a crucial role in diabetic wound healing. Diabetic hyperglycemic environments can lead to abnormal PCD in various cells during healing processes, thereby affecting the activity and function of cells and interfering with diabetic wound healing. Therefore, this review focuses on the new roles and mechanisms of PCD in diabetic wound healing. Moreover, the challenges and perspectives related to PCD in diabetic wound healing are presented, which will bring new insights to improve diabetic wound healing.

Epilepsy, a functional disease caused by abnormal discharge of neurons, has attracted the attention of neurologists due to its complex characteristics. N6-methyladenosine (m6A) is a reversible mRNA modification that plays essential role in various biological processes. Nevertheless, no previous study has systematically evaluated the role of m6A regulators in epilepsy. Here, using gene expression screening in the Gene Expression Omnibus GSE143272, we identified seven significant m6A regulator genes in epileptic and non-epileptic patients. The random forest (RF) model was applied to the screening, and seven m6A regulators (HNRNPC, WATP, RBM15, YTHDC1, YTHDC2, CBLL1, and RBMX) were selected as the candidate genes for predicting the risk of epilepsy. A nomogram model was then established based on the seven-candidate m6A regulators. Decision curve analysis preliminarily showed that patients with epilepsy could benefit from the nomogram model. The consensus clustering method was performed to divide patients with epilepsy into two m6A patterns (clusterA and clusterB) based on the selected significant m6A regulators. Principal component analysis algorithms were constructed to calculate the m6A score for each sample to quantify the m6A patterns. Patients in clusterB had higher m6A scores than those in clusterA. Furthermore, the patients in each cluster had unique immune cell components and different cell death patterns. Meanwhile, based on the M6A classification, a correlation between epilepsy and glucose metabolism was laterally verified. In conclusion, the m6A regulation pattern plays a vital role in the pathogenesis of epilepsy. The research on m6A regulatory factors will play a key role in guiding the immune-related treatment, drug selection, and identification of metabolism conditions and mechanisms of epilepsy in the future.

Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal-dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration.

Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA-cGAS-STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu. Cu thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS-STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.

Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF's anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate-copper complex (CuET).

In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward -mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter is synthetic lethal to UM4118. is misspliced and down-regulated in -mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued -mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of -mutated AMLs. We thus propose mutations as a biomarker for future copper ionophore-based therapies.

The effectiveness of chemodynamic therapy (CDT) in cancer treatment is limited by insufficient endogenous HO levels in tumor tissue and an increasing ratio of high valence metal ions. To overcome these challenges, a novel nanotherapeutic approach, named GOx-CuCaP-DSF, has been proposed. This approach involves the design of nanotherapeutics that aim to self-supply HO within cancer cells and provide a supplement of low valence metal ions to enhance the performance of CDT. GOx-CuCaP-DSF nanotherapeutics are engineered by incorporating glucose oxidase (GOx) into Ca-doped calcium phosphate (CaP) nanoparticles and loading disulfiram (DSF) through surface adsorption. Under the tumor microenvironment, GOx catalyzes the conversion of tumor-overexpressed glucose (Glu) to liberate HO. The degradation of CaP further lowers the pH, facilitating the release of Cu ions and DSF. The rapid reaction between Cu and DSF leads to the generation of Cu, increasing the Cu/Cu ratio and promoting the Cu-based Fenton reaction, which enhances the efficiency of CDT. Simultaneously, DSF undergoes conversion to diethyldithiocarbamate acid (ET), forming a copper(II) complex (Cu(II)ET) by strong chelation with Cu ions. This Cu(II)ET complex, a potent chemotherapeutic drug, exhibits a synergistic therapeutic effect in combination with CDT. Moreover, the elevated Cu species resulting from DSF reaction promotes the aggregation of toxic mitochondrial proteins, leading to cell cuproptosis. Overall, the strategy of integrating the chemodynamic therapy efficiency of the Fenton reaction with the activation of efficacious cuproptosis using a chemotherapeutic drug presents a promising avenue for enhancing the effectiveness of multi-modal anti-tumor treatments.

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays a master role in blocking ferroptosis by eliminating phospholipid hydroperoxides, the regulation of GPX4 remains poorly understood. Here, we report an unexpected role for copper in promoting ferroptotic cell death, but not cuproptosis, by inducing macroautophagic/autophagic degradation of GPX4. Copper chelators reduce ferroptosis sensitivity but do not inhibit other types of cell death, such as apoptosis, necroptosis, and alkaliptosis. Conversely, exogenous copper increases GPX4 ubiquitination and the formation of GPX4 aggregates by directly binding to GPX4 protein cysteines C107 and C148. TAX1BP1 (Tax1 binding protein 1) then acts as an autophagic receptor for GPX4 degradation and subsequent ferroptosis in response to copper stress. Consequently, copper enhances ferroptosis-mediated tumor suppression in a mouse model of pancreatic cancer tumor, whereas copper chelators attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into the link between metal stress and autophagy-dependent cell death. CALCOCO2, calcium binding and coiled-coil domain 2; GPX4, glutathione peroxidase 4; MAP1LC3A/B, microtubule associated protein 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear receptor coactivator 4; OPTN, optineurin; PDAC, pancreatic ductal adenocarcinoma; RIPK1, receptor interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member 1; SQSTM1, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.

Sphingolipids, a type of bioactive lipid, play crucial roles within cells, serving as integral components of membranes and exhibiting strong signaling properties that have potential therapeutic implications in anti-cancer treatments. However, due to the diverse group of lipids and intricate mechanisms, sphingolipids still face challenges in enhancing the efficacy of different therapy approaches. In recent decades, mass spectrometry has made significant advancements in uncovering sphingolipid biomarkers and elucidating their impact on cancer development, progression, and resistance. Primary sphingolipids, such as ceramide and sphingosine-1-phosphate, exhibit contrasting roles in regulating cancer cell death and survival. The evasion of cell death is a characteristic hallmark of cancer cells, leading to treatment failure and a poor prognosis. The escape initiates with long-established apoptosis and extends to other programmed cell death (PCD) forms when patients experience chemotherapy, radiotherapy, and/or immunotherapy. Gradually, supportive evidence has uncovered the fundamental molecular mechanisms underlying various forms of PCD leading to the development of innovative molecular, genetic, and pharmacological tools that specifically target sphingolipid signaling nodes. In this study, we provide a comprehensive overview of the sphingolipid biomarkers revealed through mass spectrometry in recent decades, as well as an in-depth analysis of the six main forms of PCD (apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis) in aspects of tumorigenesis, metastasis, and tumor response to treatments. We review the corresponding small-molecule compounds associated with these processes and their potential implications in cancer therapy.

Increasing infiltration of CD8 T cells can enhance the response rate to immune checkpoint blockade (ICB) therapies. In contrast, immunogenic cell death (ICD) induced by intracellular reactive oxygen species (ROS) is an effective strategy to increase CD8 T cell infiltration. Cuproptosis is newly defined and reported by Tsvetkov et al. A Cu-coordinated covalent organic framework (COF) in which two valence states of copper ions are simultaneously loaded is prepared. On the one hand, Cu undergoes a valence shift generating Cu which acts as an effective Fenton-like reagent to catalyze the production of OH and O from cellular overexpressed H O , causing DNA damage and lipid peroxidation (LPO), which directly produce cytotoxicity. On the other hand, residual Cu can effectively deplete endogenous cellular glutathione (GSH), converting it into glutathione disulfide (GSSG), further increasing intracellular oxidative stress and reducing the scavenging of ROS, thus further enhancing the Fenton-like effect and bringing toxic effects on tumor cells. The synergy of these two functions achieves ICD, helping for transforming "cold tumor" into "hot tumor" and efficient anti-tumor effects eventually. This work provides new insights into coordinated COF and inspire the development of more versatile COF for biomedical applications.

Cell death is a fundamental biological process, and its fine-tuned regulation is required for life. However, the complexity of regulated cell death is often reduced to a matter of live-dead discrimination. Here, we provide a perspective on programmed or regulated cell death, focusing on apoptosis, pyroptosis, necroptosis, and ferroptosis (the latter three cell death modalities are examples of regulated necrosis). We also touch on other, recently described manifestations of (pathological) cell death including cuproptosis. Furthermore, we address how engineered nanomaterials impact on regulated cell death. We posit that an improved understanding of nanomaterial-induced perturbations of cell death may allow for a better prediction of the consequences of human exposure and could also yield novel approaches by which to mitigate these effects. Finally, we provide examples of the harnessing of nanomaterials to achieve cancer cell killing through the induction of regulated cell death.

Disulfiram (DSF) is used to treat non‑small cell lung cancer (NSCLC). DSF significantly increases expression of programmed death‑ligand 1 (PD‑L1), which may enhance immunosuppression and immune escape of tumors. Therefore, the present study aimed to investigate the role of combined treatment of DSF and anti‑PD‑L1 in NSCLC resistance. The viability and apoptosis of A549 cells were detected by the Cell Counting Kit‑8 assay and flow cytometry, respectively. The expression levels of ATPase copper‑transporting β (ATP7B) and PD‑L1 in A549 cells were detected by reverse transcription‑quantitative PCR and western blot analysis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) in A549 cells were detected by respective assay kits. The expression levels of cuproptosis‑associated proteins ferredoxin‑1 (FDX1), ATP7B, solute carrier family 31 member 1 (SLC31A1), succinate dehydrogenase B (SDHB), PD‑L1 and hypoxia inducible factor (HIF)‑1A were analyzed by western blotting in A549 cells. DSF inhibited the viability of A549 cells and promoted expression levels of ATP7B and PD‑L1 at both mRNA and protein levels in A549 cells. The viability of cisplatin (DPP)‑treated A549 cells was increased following DSF treatment. JQ‑1 (a PD‑L1 inhibitor) suppressed the viability of DPP‑treated A549 cells pretreated with DSF. DSF increased expression levels of ATP7B and PD‑L1. The combination treatment of DSF and JQ‑1 in A549 cells increased levels of ROS and MDA, as well as expression levels of FDX1 and SLC31A1; however, combination treatment decreased levels of SOD, as well as expression levels of ATP7B, SDHB, PD‑L1, and HIF‑1A. PX478 (an HIF‑1 inhibitor) acted with DSF to enhance the inhibitory effects on the viability and on the induction of apoptosis of A549 cells. PX478 upregulated the levels of ROS and MDA, while it downregulated levels of SOD in DSF‑treated A549 cells. PX478 promoted expression levels of FDX1 and SLC31A1, while it suppressed expression levels of ATP7B, PD‑L1, and HIF‑1A in DSF‑treated A549 cells. In conclusion, the combined treatment of A549 cells with anti‑PD‑L1 and DSF enhanced the effect of cuproptosis on the inhibition of NSCLC cell viability.

Lipoylated dihydrolipoamide S-acetyltransferase (DLAT), the component E2 of the multi-enzyme pyruvate dehydrogenase complex, is one of the key molecules of cuproptosis. However, the prognostic value and immunological role of DLAT in pan-cancer are still unclear. Using a series of bioinformatics approaches, we studied combined data from different databases, including the Cancer Genome Atlas, Genotype Tissue-Expression, the Cancer Cell Line Encyclopedia, Human Protein Atlas, and cBioPortal to investigate the role of DLAT expression in prognosis and tumor immunity response. We also reveal the potential correlations between DLAT expression and gene alterations, DNA methylation, copy number variation (CNV), tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune infiltration levels, and various immune-related genes across different cancers. The results show that DLAT displays abnormal expression within most malignant tumors. Through gene set enrichment analysis (GSEA), we found that DLAT was significantly associated with immune-related pathways. Further, the expression of DLAT was also confirmed to be correlated with the tumor microenvironment and diverse infiltration of immune cells, especially tumor-associated macrophages (TAMs). In addition, we found that DLAT is co-expressed with genes encoding major histocompatibility complex (MHC), immunostimulators, immune inhibitors, chemokines, and chemokine receptors. Meanwhile, we demonstrate that DLAT expression is correlated with TMB in 10 cancers and MSI in 11 cancers. Our study reveals that DLAT plays an essential role in tumorigenesis and cancer immunity, which may be used to function as a prognostic biomarker and potential target for cancer immunotherapy.

Copper ions play a crucial role as cofactors for essential enzymes in cellular processes. However, when the intracellular concentration of copper ions exceeds the homeostatic threshold, they become toxic to cells. In our study, we demonstrated that elesclomol, as a carrier of copper ions, caused an upregulation of protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), which plays a role in regulating substrate selectivity of protein phosphatase 1 during cuproptosis. Mechanistically, we investigated that PPP1R15A activated translation initiation by dephosphorylating eukaryotic translation initiation factor 2 subunit alpha at the S51 residue through protein phosphatase 1 and phosphorylating eukaryotic translation initiation factor 4E binding protein 1 at the T70 residue. In addition, PPP1R15A reduced H3K4 methylation by altering the phosphorylation of histone methyltransferases, which led to the silencing of MYC and G2M phase arrest.

Cuproptosis is a unique type of cell death that may influence tumour formation by targeting lipoylated tricarboxylic acid cycle proteins. Solute carrier family 31 member 1 (SLC31A1), an important copper transporter, influences dietary copper absorption in the cell membrane. However, various SLC31A1 properties in pan-cancer profiles remain unknown. This study investigated the role of SLC31A1 in human malignancies and analysed its prognostic value. Raw data were obtained from The Cancer Genome Atlas database and processed using numerous internet databases, including UALCAN, GEPIA, cBioPortal, TIMER2.0, and Human Protein Atlas. SLC31A1 expression was found to be elevated in cervical, endometrial, and breast cancers compared to that in normal tissues, but reduced in clear cell renal cell carcinoma, liver hepatocellular carcinoma, and lung adenocarcinoma. Furthermore, SLC31A1 expression was strongly associated with overall survival and disease-free survival in several cancers. SLC31A1 gene mutations and methylations were identified in 33 cancers. SLC31A1 expression was positively correlated with immune cells in immune infiltration data. Single-cell sequencing revealed that SLC31A1 may play key roles in DNA repair, DNA damage, and proliferation. These findings may lead to better understanding of SLC31A1 in pan-cancer profiles and suggest that SLC31A1 could be a viable predictive biomarker, particularly in gynaecological cancers.

Pyroptosis, a new mode of regulatory cell death, holds a promising prospect in tumor therapy. The occurrence of pyroptosis can trigger the release of damage-associated molecular patterns (DAMPs) and activate the antitumor immune response. Moreover, enhancing intracellular reactive oxygen species (ROS) generation can effectively induce pyroptosis. Herein, an integrated nanoplatform (hCZAG) based on zeolitic imidazolate framework-8 (ZIF-8) with Cu and Zn as active nodes and glucose oxidase (GOx) loading is constructed to evoke pyroptosis. GOx can effectively elevate intracellular hydrogen peroxide (HO) levels to regulate the unfavorable tumor microenvironment (TME). Cu can be reduced to Cu by endogenous overexpressed GSH and both Cu and Cu can exert Fenton-like activity to promote ROS generation and amplify oxidative stress. In addition, the accumulation of Cu leads to the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), thus resulting in cuproptosis. Notably, the outburst of ROS induced by hCZAG activates Caspase-1 proteins, leads to the cleavage of gasdermin D (GSDMD), and induces pyroptosis. Pyroptosis further elicits an adaptive immune response, leading to immunogenic cell death (ICD). This study provides effective strategies for triggering pyroptosis-mediated immunotherapy and achieving improved therapeutic effects.

The incidence of melanoma, the most lethal form of skin cancer, has increased due to ultraviolet exposure. The treatment of advanced melanoma, particularly metastatic cases, remains challenging with poor outcomes. Targeted therapies involving BRAF/MEK inhibitors and immunotherapy based on anti-PD1/anti-CTLA4 antibodies have achieved long-term survival rates of approximately 50% for patients with advanced melanoma. However, therapy resistance and inadequate treatment response continue to hinder further breakthroughs in treatments that increase survival rates. This review provides an introduction to the molecular-level pathogenesis of melanoma and offers an overview of current treatment options and their limitations. Cells can die by either accidental or regulated cell death (RCD). RCD is an orderly cell death controlled by a variety of macromolecules to maintain the stability of the internal environment. Since the uncontrolled proliferation of tumor cells requires evasion of RCD programs, inducing the RCD of melanoma cells may be a treatment strategy. This review summarizes studies on various types of nonapoptotic RCDs, such as autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and the recently discovered cuproptosis, in the context of melanoma. The relationships between these RCDs and melanoma are examined, and the interplay between these RCDs and immunotherapy or targeted therapy in patients with melanoma is discussed. Given the findings demonstrating melanoma cell death in response to different stimuli associated with these RCDs, the induction of RCD shows promise as an integral component of treatment strategies for melanoma.

OBJECTIVES:Cancer remains a global health challenge, necessitating the identification of novel biomarkers and therapeutic targets. Cuproptosis, a recently recognized form of cell death linked to copper metabolism, presents a promising avenue for anticancer strategies. We investigated the clinical significance of SLC31A1, a key regulator of cuproptosis, in multiple cancer types, aiming to elucidate its potential as a diagnostic biomarker, prognostic, indicator and therapeutic target. METHODS:We conducted a pan-cancer analysis through TIMER2.0, evaluating SLC31A1 expression across multiple cancer types. Survival analysis was performed using KM plotter. Expression validation was carried out using UALCAN and Human Protein Atlas (HPA) databases. Methylation analysis was conducted with the help of ULACAN and OncoDB. Mutational analysis was performed using cBioPortal database. Immune infiltration analysis via the TIMER2.0 and gene enrichment analysis via the Metascape were performed to gain insights into the potential mechanisms underlying SLC31A1's role in cancer. Finally, Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to confirm SLC31A1 expression in clinical samples. RESULTS:Out of analyzed cancer, SLC31A1 exhibited significant up-regulation and correlation with worse overall survival (OS) across Breast Cancer (BRCA), Cervical Squamous Cell Carcinoma (CESC), Head and Neck Squamous Cell Carcinoma (HNSC), and Esophageal Carcinoma (ESCA). Mutational and promoter methylation analyses further revealed that hypomethylation is the major cause of SLC31A1 overexpression among BRCA, CESC, HNSC, and ESCA. Immune infiltration analysis showed significant associations between SLC31A1 expression and the presence of CD8+ T cells, CD4+ T cells, and macrophages in the tumor microenvironment. Gene enrichment analysis provided valuable insights into potential molecular pathways in context to BRCA, CESC, HNSC, and ESCA. Furthermore, when SLC31A1 was analyzed using clinical samples through RT-qPCR, this gene showed promising diagnostic potential, reflected by high Area Under the Curve (AUC) values. CONCLUSION:Our pan-cancer study highlights the up-regulation of SLC31A1 and its correlation with worse OS in BRCA, CESC, HNSC, and ESCA. In sum, outcomes of this study showed that SLC31A1 could be a potential biomarker and novel therapeutic target of BRCA, CESC, HNSC, and ESCA.

Platinum-based chemotherapy is widely used to treat various cancers. However, exogenous platinum is likely to cause severe side effects and drug resistance induced by upregulated glutathione (GSH) in cancer cells poses a threat to the management of cancer progression and recurrence. Anticancer copper-organic complexes are excellent candidates to substitute platinum-based chemotherapeutics, exhibiting lower systemic toxicity and even overcoming platinum-based chemotherapy resistance. Here, we report the GSH-resistance of copper(II) bis(diethyldithiocarbamate) (CuET) and its reversal of cisplatin resistance in non-small-cell lung cancer cuproptosis. Electrochemistry and UV-vis spectroscopy studies demonstrate that CuET possesses a lower reduction potential and the reaction inertness with GSH. Importantly, CuET overcomes the drug resistance of A549/DDP cells and the anticancer effect is hardly affected by intracellular GSH levels. To improve the solubility and bioavailability, bovine serum albumin-stabilized CuET nanoparticles (NPs) are prepared and they have a high drug loading content of 27.5% and excellent physiological stability. studies manifest that CuET NPs augment the distributions in the cytosol and cytoskeleton, inducing cell death cuproptosis in A549/DDP cells, which is distinctly different from the apoptosis pattern induced by cisplatin. antitumor evaluation shows that the nanomedicine has superior biosafety and potent antitumor activity in a cisplatin-resistant tumor model. Our study suggests that copper-organic complex-based nanosystems could be a powerful toolbox to tackle the platinum-based drug resistance and systemic toxicity concerns.

Background:Cancer affects millions of people each year and imposes a huge economic and social burden worldwide. Cuproptosis is a recently discovered novel mode of cell death. The exact function of the cuproptosis-related gene dihydrolipoamide dehydrogenase (DLD) and its role in pan-cancer is unknown. Methods:Data were retrieved from the GTEx, TCGA, and multiple online websites. These data were used to assess the expression, prognosis, and diagnostic value of DLD in various tumors. The relationship of DLD with immune microenvironment immunomodulators, immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI), and oncology drug sensitivity was explored by correlation analysis. Results:The mRNA and protein expression of DLD differs in most cancers. Survival analysis showed that DLD was associated with prognosis with KIRC, KIRP, KICH, and UCS. DLD had a strong diagnostic value in KIRC, GBM, PAAD, and LGG (AUC > 0.9). DLD promoter methylation affects the aberrant expression of LIHC, LUSC, PAAD, READ, and THCA. DLD was negatively correlated with stromal score, immune score, and ESTIMATE score in UCEC, TGCT, LUSC, and SARC. In UCS, resting memory CD4 T cells and activated NK cells were significantly correlated with DLD expression. Significant correlations were also observed between DLD expression and immunomodulators, immune checkpoints, TMB, and MSI in various cancers. Importantly, we also identified a number of potential drugs that may target DLD. Conclusion:DLD expression is associated with a variety of tumor prognoses and plays an integral role in tumorigenesis, tumor metabolism, and immunity.

Ferredoxin 1 (FDX1) functions by transferring electrons from NADPH to mitochondrial cytochrome P450 via the ferredoxin reductase and is the key regulator in copper-dependent cell death. Although mounting evidence supports a vital role for FDX1 in tumorigenesis of some cancers, no pan-cancer analysis of FDX1 has been reported. Therefore, we aimed to explore the prognostic value of FDX1 in pan-cancer and investigate its potential immune function. Based on data from The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, Human Protein Atlas, and Gene Set Cancer Analysis, we used a range of bioinformatics approaches to explore the potential carcinogenic role of FDX1, including analyzing the relationship between FDX1 expression and prognosis, DNA methylation, RNA methylation-related genes, mismatch repair (MMR) gene, microsatellite instability (MSI), tumor mutation burden (TMB), tumor microenvironment (TME), immune-related genes, and drug sensitivity in different tumors. The results show that FDX1 was lowly expressed in most cancers but higher in glioblastoma multiforme, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Moreover, FDX1 expression was positively or negatively associated with prognosis in different cancers. FDX1 expression was significantly associated with DNA methylation in 6 cancers, while there was a correlation between FDX1 expression and RNA methylation-related genes and MMR gene in most cancers. Furthermore, FDX1 expression was significantly associated with MSI in 8 cancers and TMB in 10 cancers. In addition, FDX1 expression was also significantly correlated with immune cell infiltration, immune-related genes, TME, and drug resistance in various cancers. An experiment showed FDX1 is downregulated by elesclomol, resulting in inhibiting cell viability of bladder cancer, clear cell renal cell carcinoma, and prostate cancer cells. Our study reveals that FDX1 can serve as a potential therapeutic target and prognostic marker for various malignancies due to its vital role in tumorigenesis and tumor immunity.

Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.

Drug resistance is one of the leading causes of treatment failure in current cancer chemotherapy. In addition to the classical drug efflux transporter-mediated chemoresistance, cancer cells with stemness features play a crucial role in escaping the maximum impact of chemotherapy. To sensitize cancer chemotherapy, in a novel approach, the hedgehog pathway inhibitor ellagic acid (EA) is coordinated with Cu to develop nanoscale metal-organic frameworks (EA-Cu), which are then loaded with doxorubicin (DOX) and modified with targeted chondroitin sulfate (CS) to form the CS/E-C@DOX nanoplatform (CS/NPs). Notably, EA inhibits stemness maintenance by suppressing the hedgehog pathway, while Cu further decreases stemness features of tumor cells by disrupting mitochondrial metabolism, effectively enhancing DOX-mediated chemotherapy. Meanwhile, EA can act synergistically with Cu to cause mitochondrial dysfunction and cuproptosis, which effectively decreases ATP levels and subsequently suppresses the activity of P-glycoprotein (P-gp), thus reducing drug efflux and sensitizing DOX-mediated chemotherapy. Additionally, the attached CS endows CS/NPs with specific tumor targeting properties, whereas EA-Cu endows this nanoplatform with pH/glutathione (GSH) dual-responsive release behavior. Taken together, CS/NPs exhibited excellent antitumor effects by inducing cuproptosis and significantly inhibiting cancer cell stemness, which has great potential for overcoming cancer chemoresistance.

As a transitional metal, copper plays a crucial role in maintaining the normal physiological activities of mammals. The intracellular copper concentration is meticulously regulated to maintain extremely low levels through homeostatic regulation. Excessive accumulation of free copper in cells can have deleterious effects, as observed in conditions such as Wilson's disease. Moreover, data accumulated over the past few decades have revealed a crucial role of copper imbalance in tumorigenesis, progression and metastasis. Recently, cuproptosis, also known as copper-induced cell death, has been proposed as a novel form of cell death. This discovery offers new prospects for treating copperrelated diseases and provides a promising avenue for developing copper-responsive therapies, particularly in cancer treatment. We present a comprehensive overview of the Yin- Yang equilibrium in copper metabolism, particularly emphasising its pathophysiological alterations and their relevance to copper-related diseases and malignancies.

Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r relaxivity, allowing for T-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.

Multimodal combined therapy (MCT) is an emerging avenue to eliminate tumor cells by the synergistic effect of various therapeutic methods. However, the complex tumor microenvironment (TME) is becoming the key barrier to the therapeutic effect of MCT due to the excessive existence of H ions, HO, and glutathione (GSH), the lack of O, and the relaxation of ferroptosis. To overcome these limitations, smart nanohybrid gels with excellent biocompatibility, stability and targeting function were prepared by using gold nanoclusters as cores and an in situ cross-linking composite gel of sodium alginate (SA)/hyaluronic acid (HA) as the shell. The obtained Au NCs-Cu@SA-HA core-shell nanohybrid gels possessed near-infrared light response synergistically benefitting photothermal imaging guided photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the H-triggered release of Cu ions from the nanohybrid gels not only induces cuproptosis to avoid the relaxation of ferroptosis, but also catalyzes HO in the TME to generate O to simultaneously improve the hypoxic microenvironment and PDT effect. Furthermore, the released Cu ions could consume the excessive GSH to form Cu ions effectively, which caused the formation of hydroxyl free radicals (·OH) to kill tumor cells, synergistically realizing GSH consumption-enhanced PDT and chemodynamic therapy (CDT). Hence, the novel design in our work provides another research avenue for cuproptosis-enhanced PTT/PDT/CDT via TME modulation.

Cancer immunotherapy has become a mainstream cancer treatment over traditional therapeutic modes. Cancer cells can undergo programmed cell death including ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis which are find to have intrinsic relationships with host antitumor immune response. However, direct use of cell death inducers or regulators may bring about severe side effects that can also be rapidly excreted and degraded with low therapeutic efficacy. Nanomaterials are able to carry them for long circulation time, high tumor accumulation and controlled release to achieve satisfactory therapeutic effect. Nowadays, a large number of studies have focused on nanomedicines-based strategies through modulating cell death modalities to potentiate antitumor immunity. Herein, immune cell types and their function are first summarized, and state-of-the-art research progresses in nanomedicines mediated cell death pathways (e.g., ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis) with immune response provocation are highlighted. Subsequently, the conclusion and outlook of potential research focus are discussed.

This study aims to visualize research hotspots and trends of "ferroptosis in cancer", "necroptosis in cancer", "pyroptosis in cancer", and "cuproptosis in cancer" through a bibliometric analysis to facilitate understanding of future developments in basic and clinical research and to provide a new perspective on cancer treatment. From January 1, 2012 to October 31, 2022, in the field of "ferroptosis in cancer", a total of 2467 organizations from 79 different countries published 3302 articles. 2274 organizations from 72 different countries published 2233 articles in the field of " necroptosis in cancer". 1366 institutions from 58 different countries contributed 1445 publications in the field of "pyroptosis in cancer". In the field of " cuproptosis in cancer", the number of articles published in the last 10 years is relatively low, with a total of 109 articles published by 116 institutions from four different countries. In the field of "ferroptosis in cancer", Tang Daolin had published 66 documents, ranked the first, while Dixon SJ is the most cited author, cited 3148 times; In the fields of "necroptosis in cancer", Vandenabeele peter had published 35 papers and Degterev had been cited 995 times, ranked the first, respectively; Kanneganti thirumala-devi had published 24 papers, is the highest number of publications in the fields of "pyroptosis in cancer", while Shi JJ was the most cited author with being cited 508 times. Both Huang Yan and Wang Tao published three papers and tied for first place and Tsvetkov p ranks first with being cited 107 times in "cuproptosis in cancer". "Cell", "Cell", "Nature", and "Science" was the most frequently co-cited journal on "ferroptosis in cancer", "necroptosis in cancer", "pyroptosis in cancer", and "cuproptosis in cancer", respectively. Further exploration of inhibitors of different Programmed cell death (PCD) and their targeted therapies are potential treatment options for cancer, but more direct clinical evidence as well as higher level clinical trials remain to be explored. Further clarification of the mechanisms of crosstalk between these PCDs may provide effective cancer treatments. And the role of different types of PCDs, especially the novel ones discovered, in cancer can be expected to remain a hot topic of research in the cancer field for quite some time to come.

Copper (Cu) plays a crucial and diverse function in biological systems, acting as a cofactor at numerous sites of enzymatic activity and participating in various physiological processes, including oxidative stress regulation, lipid metabolism, and energy metabolism. Similar to other micronutrients, the body regulates Cu levels to ensure homeostasis; any disruption in Cu homeostasis may result in various illnesses. Cuproptosis causes proteotoxic stress and ultimately results in cell death by the binding of Cu ions to lipid-acylated proteins during the tricarboxylic acid cycle of mitochondrial respiration. Cu is not only involved in regulatory cell death (RCD), but also in exogenous factors that induce cellular responses and toxic outcomes. Cu imbalances also affect the transmission of several RCD messages. Therefore, this article presents a thorough examination of the mechanisms involved in Cu-induced RCD as well as the role of Cu complexes in its pathophysiology.

The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.

Introduction:Bladder cancer (BLCA) is the ninth most common malignancy worldwide and the fourth most common cancer in men. Copper levels are significantly altered in patients with thyroid, breast, lung, cervical, ovarian, pancreatic, oral, gastric, bladder, and prostate cancers. Outcomes can be predicted by constructing signatures using lncRNA-related genes associated with outcomes. Methods:We identified lncRNAs related to outcomes, those differentially expressed in bladder cancer, and cuproptosis-related lncRNAs from TCGA. We identified the intersection to obtain 12 genes and established a prognostic risk signature consisting of eight genes using LASSO-penalized multivariate Cox analysis. We constructed a training set, performed survival analysis on the high-and low-risk groups, and performed validation in the test and full sets. There existed a substantial contrast in the likelihood of survival among the cohorts of high and low risk. An in-depth analysis of the gene mutations associated with tumors was conducted to evaluate the risk of developing cancer. We also performed gene analysis on neoadjuvant chemotherapy. We conducted experimental validation on the key gene UBE2Q1-AS1 in our prognostic signature. Results:The risk signature we constructed shows significant differences between the high-risk group and the low-risk group. Univariate survival analysis of the eight genes in our signature showed that each gene distinguished between high- and low-risk groups. Sub-group analysis revealed that our risk score differed significantly in tumor stage, age, and gender. The analysis results of the tumor mutation burden (TMB) showed a significant difference in the TMB between the low- and high-risk groups, which had a direct impact on the outcomes. These findings highlight the importance of TMB as a potential prognostic marker in cancer detection and prevention. We analyzed the immune microenvironment and found significant differences in immune function, validation responses, immunotherapy-related positive markers, and critical steps in the tumor immunity cycle between the high- and low-risk groups. We found that the effect of anti-CTLA4 and PD-1 was higher in the high-risk group than in the low-risk group.Gene analysis of neoadjuvant chemotherapy revealed that the treatment effect in the high-risk group was better than in the low-risk group. The key gene UBE2Q1-AS1 in our prognostic signature can significantly influence the cell viability, migration, and proliferation of cancer cells. Discussion:We established a signature consisting of eight genes constructed from cuproptosis-related lncRNAs that have potential clinical applications for outcomes prediction, diagnosis, and treatment.

Recent studies have identified a novel programmed cell death based on copper, named cuproptosis. However, as an anti-cuproptosis gene, the functional roles, definite mechanisms and prognostic value of CDKN2A in pan-cancer are largely unclear. The GEPIA2, cancer genome atlas (TCGA), the tumor immune estimation resource 2.0 and CPTAC databases were performed to validate the differential expression of CDKN2A in 33 tumors. The clinical features and survival prognosis analysis were conducted by GEPIA2 and UALCAN web tool. Genetic alteration analysis of CDKN2A in pan-cancer was also evaluated. Furthermore, the functional roles of CDKN2A were explored via DNA methylation analysis, tumor microenvironment, infiltration of immune cells, enrichment analysis and gene co-expression associated with cuproptosis and immune regulation. The CDKN2A expression, both at the transcriptional and translational level, was obviously upregulated in most cancer patients, which might lead to poor survival in certain cancer types. CDKN2A expression was significantly associated with tumor pathological stages in some cancer types. In adrenocortical carcinoma (ACC) and kidney renal clear cell carcinoma (KIRC), DNA methylation of CDKN2A was explored to induce poor clinical outcomes. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis indicated that CDKN2A expression was closely related to several cancer-associated signaling pathways, such as the p53 signaling pathway, Cellular senescence, DNA replication and Cell cycle signaling pathways. Gene set enrichment analysis (GSEA) analysis suggested that aberrantly expressed CDKN2A took part in the cell cycle regulation, immune regulation and mitochondrial signaling pathways in certain cancer patients. In addition, aberrant CDKN2A expression was closely correlated to immune infiltration and the levels of immune-regulatory genes. The study deeply defined the concrete roles of cuproptosis-related gene CDKN2A in tumorigenesis. The results provided new insights and pieces of evidence for treatment.

Cognitive dysfunction occurs mainly in certain diseases and in the pathological process of aging. In addition to this, it is also widespread in patients undergoing anesthesia, surgery, and cancer chemotherapy. Neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired synaptic plasticity, and lack of neurotrophic support are involved in copper-induced cognitive dysfunction. In addition, recent studies have found that copper mediates cuproptosis and adversely affects cognitive function. Cuproptosis is a copper-dependent, lipoylated mitochondrial protein-driven, non-apoptotic mode of regulated cell death, which provides us with new avenues for identifying and treating related diseases. However, the exact mechanism by which cuproptosis induces cognitive decline is still unclear, and this has attracted the interest of many researchers. In this paper, we analyzed the pathological mechanisms and therapeutic targets of copper-associated cognitive decline, mainly in the context of neurodegenerative diseases, psychiatric and psychological disorders, and diabetes mellitus.

Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.

Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act as constituents of metalloenzymes involved in cellular metabolism, function as signaling molecules to regulate the proliferation and metastasis of tumors, and are integral components of metal-based anticancer drugs. Notably, recent research reveals that excessive copper can also modulate the occurrence of programmed cell death (PCD), known as cuprotosis, in cancer cells. This modulation occurs through the disruption of tumor cell metabolism and the induction of proteotoxic stress. This discovery uncovers a mode of interaction between transition metals and proteins, emphasizing the intricate link between copper homeostasis and tumor metabolism. Moreover, they provide innovative therapeutic strategies for the precise diagnosis and treatment of malignant tumors. At the crossroads of chemistry and oncology, we undertake a comprehensive review of copper homeostasis in tumors, elucidating the molecular mechanisms underpinning cuproptosis. Additionally, we summarize current nanotherapeutic approaches that target cuproptosis and provide an overview of the available laboratory and clinical methods for monitoring this process. In the context of emerging concepts, challenges, and opportunities, we emphasize the significant potential of nanotechnology in the advancement of this field.

Cancer has always been a worldwide problem, and the application of radiotherapy has greatly improved the survival rate of cancer patients. Radiotherapy can modulate multiple cell fate decisions to kill tumor cells and achieve its therapeutic effect. With the development of radiotherapy technology, how to increase the killing effect of tumor cells and reduce the side effects on normal cells has become a new problem. In this review, we summarize the mechanisms by which radiotherapy induces tumor cell apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, autophagy, senescence, mitotic catastrophe, and cuproptosis. An in-depth understanding of these radiotherapy-related cell fate decisions can greatly improve the efficiency of radiotherapy for cancer.

Regulated Cell Death (RCD) is a mode of cell death that occurs through drug or genetic intervention. The regulation of RCDs is one of the significant reasons for the long survival time of tumor cells and poor prognosis of patients. Long non-coding RNAs (lncRNAs) which are involved in the regulation of tumor biological processes, including RCDs occurring on tumor cells, are closely related to tumor progression. In this review, we describe the mechanisms of eight different RCDs which contain apoptosis, necroptosis, pyroptosis, NETosis, entosis, ferroptosis, autosis and cuproptosis. Meanwhile, their respective roles in the tumor are aggregated. In addition, we outline the literature that is related to the regulatory relationships between lncRNAs and RCDs in tumor cells, which is expected to provide new ideas for tumor diagnosis and treatment.