Endoplasmic reticulum stress inhibitor may substitute for sleeve gastrectomy to alleviate metabolic dysfunction-associated steatotic liver disease. Clinics and research in hepatology and gastroenterology BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most common form of chronic liver disease worldwide. We explored the potential mechanisms responsible for the protective role of sleeve gastrectomy (SG) on MASLD in a high-fat diet (HFD) rat model. METHODS:Rats were fed with HFD for 12 weeks to generate MASLD model that were subjected to SG or sham surgery. The endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (4-PBA) was injected intraperitoneally every day for 4 weeks after surgery to identify the impact of ERS. RESULTS:The MASLD rat model was generated successfully, as indicated by significant upregulation of metabolic parameters. Fibroblast growth factor 21 (FGF21) and ERS-related proteins were increased in HFD rats, while expression of fibroblast growth factor receptor 1 was decreased as expected. An HFD also induced swelling and blurring of the endoplasmic reticulum and mitochondria in hepatocytes, and the above transformation could be relieved by SG and 4-PBA. SG and an ERS inhibitor both inhibited MASLD, but their combined treatment had no additional benefit. CONCLUSIONS:Dysfunction of the FGF21 signaling pathway and hepatic steatosis and inflammation could be induced by an HFD, potentially causing MASLD. Bariatric surgery and ERS inhibition could alleviate MASLD by relieving ERS-mediated impairment of FGF21 signal transduction. These findings provide a new insight into the use of ERS inhibitors to treat MASLD, especially in patients who prefer to avoid surgery. 10.1016/j.clinre.2023.102229