<p>Suppressor of glucose by autophagy (SOGA1), a lipid regulator, reprograms energy metabolism in the liver. However, whether SOGA1 is involved in the progression of nonalcoholic steatohepatitis (NASH) remains unclear. In this study, mice were fed a high-fat diet to construct a NASH mouse model with liver fibrosis, and the results showed that SOGA1 was upregulated in liver tissues of NASH mice. Hepatocytes (NCTC1469 cells) were treated with palmitic acid (PA), and the supernatant was isolated as conditioned medium (CM) to culture hepatic stellate cells (JS1 cells), simulating NASH in vitro. SOGA1 loss of function experiments showed that silencing SOGA1 decreased the levels of inflammatory factors (TNF-α and IL-6), fibrosis markers (α-SMA, COL1A1 and TGF-β1), senescence markers (p53, p21, γ-H2AX) and mitochondrial fusion markers (OPA1, MFN1, and MFN2), and elevated the levels of mitochondrial fission marker DRP1 and autophagy related protein LC3-II/I in PA-treated NCTC1469 cells. Furthermore, CM from SOGA1 silenced NCTC1469 cells reduced the protein levels of collagen I, III and α-SMA and decreased the viability in JS1 cells. Mechanistic studies showed that SOGA1 inhibits the activation of AMPK/mTOR pathway by recruiting RNF41, reducing mitophagy and mitochondrial homeostasis, thereby accelerating hepatocyte senescence. Senescent hepatocytes promote fibrosis by secreting IL-6 to activate hepatic stellate cells. Finally, lentiviral vectors of sh-SOGA1 were injected into NASH mice and found that SOGA1 knockout alleviated NASH progression in mice. In conclusion, SOGA1 knockdown may inhibit hepatocyte senescence and hepatic stellate cell activation by enhancing AMPK/mTOR-mediated mitochondrial homeostasis, thereby alleviating NASH progression.</p> Graphical Abstract <p></p>