Up-regulation of TRIM38 by alpha-hederin inhibits endoplasmic reticulum stress and improves liver fibrosis

Liver fibrosis is a critical step in the progression of chronic liver disease. Its core mechanism involves the abnormal activation and excessive proliferation of hepatic stellate cells (HSCs). alpha-Hederin is a triterpenoid saponin compound extracted from Hedera helix L. It exhibits multiple pharmacological activities, including anti-inflammatory and anti-tumor effects. However, its mechanism of action in combating liver fibrosis is unclear. The objective of this study is to investigate whether alpha-hederin alleviates endoplasmic reticulum stress (ERS) by regulating the expression of the E3 ubiquitin ligase TRIM38, thereby inhibiting HSC activation and liver fibrosis progression. First, the CCK-8 assay determined the non-toxic concentration of alpha-hederin for LX-2 cells to be 10 ug/mL, and this concentration was used in subsequent experiments. In TGF-beta1-induced liver fibrosis in LX-2 cells, alpha-hederin treatment significantly inhibited HSCs activation, as evidenced by down-regulation of alpha-SMA and suppressed proliferation capacity. Transcriptome sequencing analysis revealed that alpha-hederin treatment significantly upregulated TRIM38 expression. Differentially expressed genes (DEGs) were significantly enriched in endoplasmic reticulum stress-related pathways. Establishing stable cell lines that over-express or knockdown TRIM38 confirmed that TRIM38 up-regulation inhibits HSC activation and proliferation, reducing the expression of ERS marker proteins (GRP78, p-PERK, and CHOP). Further rescue experiments demonstrated that TRIM38 knockdown significantly attenuated the inhibitory effects of alpha-hederin on these processes. Taken together, these findings reveal that alpha-hederin alleviates endoplasmic reticulum stress by up-regulating TRIM38 expression, which ultimately inhibits hepatic stellate cell activation and proliferation, thereby exerting anti-fibrotic effects. These findings provide novel therapeutic target and drug candidate options for treating liver fibrosis.