α-Hederin Alleviates Endoplasmic Reticulum Stress by Upregulating TRIM38 Expression, Thereby Inhibiting Hepatic Stellate Cell Activation and Liver Fibrosis.

Objectives: This study aims to investigate the potential molecular mechanisms by which α-hederin modulates HSC activation to alleviate liver fibrosis. Methods: An in vitro model of liver fibrosis was established by inducing LX-2 cells with TGF-β1. These cells were then treated with α-hederin (10 μg/mL) before undergoing phenotypic analysis and molecular-level detection. A mouse model of liver fibrosis induced by CCl4 was established in vivo to further evaluate the expression levels of fibrosis markers, including TRIM38. Results: In TGF-β1-induced liver fibrosis in LX-2 cells, α-hederin treatment significantly inhibited HSCs activation, as evidenced by down-regulation of α-SMA and suppressed proliferation capacity. At the same time, α-hederin significantly reduced the levels of COL1A1, COL3A1, fibronectin, and MMP-2. Transcriptome sequencing analysis revealed that α-hederin treatment significantly upregulated TRIM38 expression. Differentially expressed genes (DEGs) were significantly enriched in endoplasmic reticulum stress-related pathways. TRIM38 up-regulation inhibits HSC activation and proliferation, reducing the expression of ERS marker proteins (GRP78, p-PERK, and CHOP); Co-IP experiments further confirmed that TRIM38 and GRP78 interact directly. Further rescue experiments demonstrated that TRIM38 knockdown significantly attenuated the inhibitory effects of α-hederin on these processes. In a CCl4-induced mouse model of liver fibrosis, α-hederin (4 mg/kg) significantly reduced the liver index and serum ALT and AST levels, improved histopathological damage to the liver, upregulated TRIM38 expression in liver tissue, and inhibited the endoplasmic reticulum stress response (ERS). Conclusions: α-hederin exerts its anti-fibrotic effect by upregulating TRIM38, thereby alleviating endoplasmic reticulum stress and ultimately inhibiting the activation and proliferation of HSCs.