Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases.
Science advances
Ferroptosis is a form of iron-dependent, lipid peroxidation-driven regulatory cell death that has been implicated in the pathogenesis of multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, inhibitors that directly and specifically target ferroptosis are not yet available. Here, we identify the compound AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. Our results show that AS effectively inhibits lipid peroxidation and ferroptosis in both human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4 to inhibit its enzymatic activity, resulting in the suppression of lipid peroxidation and ferroptosis. By using nanoparticle-based delivery systems, treatment with AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). Thus, our results identify that AS is a specific and targeted inhibitor of ACSL4 with remarkable antiferroptosis function, providing a potential therapeutic for ferroptosis-related diseases.
10.1126/sciadv.adk1200
Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function.
Nature cell biology
Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.
10.1038/s41556-023-01133-9
Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA.
Cell death and differentiation
Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in the development and drug resistance of tumors. Long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be involved in the regulation of cell cycle, proliferation, apoptosis, and migration of tumor cells. However, the function and molecular mechanism of NEAT1 in regulating ferroptosis in tumors remain unclear. Here, we found that ferroptosis inducers erastin and RSL3 increased NEAT1 expression by promoting the binding of p53 to the NEAT1 promoter. Induced NEAT1 promoted the expression of MIOX by competitively binding to miR-362-3p. MIOX increased ROS production and decreased the intracellular levels of NADPH and GSH, resulting in enhanced erastin- and RSL3-induced ferroptosis. Importantly, overexpression of NEAT1 increased the anti-tumor activity of erastin and RSL3 by enhancing ferroptosis both in vitro and in vivo. Collectively, these data suggest that NEAT1 plays a novel and indispensable role in ferroptosis by regulating miR-362-3p and MIOX. Considering the clinical findings that HCC patients are insensitive to chemotherapy and immunotherapy, ferroptosis induction may be a promising therapeutic strategy for HCC patients with high NEAT1 expression.
10.1038/s41418-022-00970-9
G protein-coupled estrogen receptor activation by bisphenol-A disrupts lipid metabolism and induces ferroptosis in the liver.
Environmental pollution (Barking, Essex : 1987)
As a metabolic disruptor, bisphenol A (BPA) has been widely reported to disrupt lipid balance. Moreover, BPA has gained significant attention due to its estrogenic activity. While both ferroptosis and the G-protein-coupled estrogen receptor (GPER) have been implicated in lipid metabolism, their link to BPA-induced lipid accumulation remains unclear. In this study, chickens were randomly assigned to three groups and housed them for 4 weeks: a control group (0 μg/L BPA), a low dose group (50 μg/L BPA) and a high dose group (5000 μg/L BPA) to investigate the underlying mechanism of BPA-induced hepatotoxicity. Our results showed that BPA exposure significantly increased the contents of TG, TC, and LDL-C while decreasing HDL-C levels. We also found that BPA treatment altered the levels of genes involved in fatty acid β-oxidation (ampkα, cpt-1, and ppaα), synthesis (acc, fas, scd-1, and srebp-1) and absorption (lpl and cd36). Moreover, the results showed that the BPA group had higher levels of IL-1β, IL-18 and TNF-α. These results indicated that BPA exposure disrupted lipid metabolism and induced inflammation in the liver. We also demonstrated that BPA caused hepatic ferroptosis by raising iron content and the expression of genes related to lipid peroxidation (lpcat3, acsl4 and alox15), while reducing the expression of antioxidant system-associated genes (gpx4, slc7a11 and slc3a2). Importantly, BPA remarkably activated GPER expression in the liver. Interestingly, inhibition of GPER remarkably ameliorated BPA-induced lipid metabolism disorder, inflammatory response, and ferroptosis, indicating the crucial role of GPER in BPA-induced liver abnormalities. These findings highlight the link between GPER and ferroptosis in BPA-induced hepatotoxicity, providing new insights into the potential hazard of BPA.
10.1016/j.envpol.2023.122211
Kaempferol prevents acetaminophen-induced liver injury by suppressing hepatocyte ferroptosis Nrf2 pathway activation.
Food & function
Acetaminophen (APAP)-induced liver injury (AILI) has become a growing public health problem. Ferroptosis, an iron-dependent form of cell death associated with lipid peroxide accumulation, has been recently implicated in AILI. The activation of the Nrf2 signaling pathway is a potential therapy for AILI. Kaempferol (KA), a flavonoid widely existing in edible plants, has been reported to exert profound anti-inflammatory and antioxidant activities. This study aimed to investigate whether KA exerts anti-AILI effects the Nrf2 signaling pathway. Mice were fasted for 22 h and injected intraperitoneally with APAP (250 mg kg) to induce AILI. Mice were pre-injected intragastrically with KA for 2 h followed by APAP injection. The hepatic injury was observed by H&E staining. Biochemical parameters of the serum and liver were measured using kits. KA alleviated hepatic injury and inflammatory response in AILI mice and ameliorated APAP-induced hepatic iron overload and oxidative stress in mice. In addition, the protective effects of KA against APAP-induced hepatotoxicity were examined in L02 cells . Cell viability was assayed by the CCK8 assay. Mitochondrial reactive oxygen species (ROS) in L02 cells were detected by MitoSox fluorescence. KA reversed the APAP-induced decrease in cell viability and GSH levels and inhibited the accumulation of intracellular ROS. Furthermore, KA activated the Nrf2 pathway and upregulated Gpx4 in mouse livers and L02 cells to inhibit ferroptosis induced by APAP. Finally, molecular docking indicated the potential interaction of KA with Keap1. Taken together, KA ameliorated oxidative stress and ferroptosis-mediated AILI by activating Nrf2 signaling.
10.1039/d2fo02716j
Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury.
Cell metabolism
G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.
10.1016/j.cmet.2024.09.007
Targeting ferroptosis by poly(acrylic) acid coated MnO nanoparticles alleviates acute liver injury.
Nature communications
Ferroptosis, a newly characterized form of regulated cell death, is induced by excessive accumulation of lipid peroxidation catalyzed by intracellular bioactive iron. Increasing evidence has suggested that ferroptosis is involved in the pathogenesis of several human diseases, including acute liver injury. Targeted inhibition of ferroptosis holds great promise for the clinical treatment of these diseases. Herein, we report a simple and one-pot synthesis of ultrasmall poly(acrylic) acid coated MnO nanoparticles (PAA@MnO-NPs, PMO), which perform multiple antioxidant enzyme-mimicking activities and can scavenge broad-spectrum reactive oxygen species. PMO could potently suppress ferroptosis. Mechanistically, after being absorbed mainly through macropinocytosis, PMO are largely enriched in lysosomes, where PMO detoxify ROS, inhibit ferritinophagy-mediated iron mobilization and preserve mTOR activation, which collectively confer the prominent inhibition of ferroptosis. Additionally, PMO injection potently counteracts lipid peroxidation and alleviates acetaminophen- and ischaemia/reperfusion-induced acute liver injury in mice. Collectively, our results reveal that biocompatible PMO act as potent ferroptosis inhibitors through multifaceted mechanisms, which ensures that PMO have great translational potential for the clinical treatment of ferroptosis-related acute liver injury.
10.1038/s41467-023-43308-w