CAT1 modulates hepatic fibrosis via IL-6-mediated inflammatory and fibrogenic pathways in hepatic stellate cells.

Hepatic fibrosis is characterized by excessive extracellular matrix deposition and chronic inflammation, primarily driven by the activation of hepatic stellate cells (HSCs). The cationic amino acid transporter 1 (CAT1) has been identified as a key regulator of HSCs activation and fibrosis progression, but its interaction with inflammatory pathways remains unclear. This study investigated the role of CAT1 in hepatic fibrosis and its regulatory effect on interleukin-6 (IL-6)-mediated inflammatory and fibrogenic responses. Bioinformatic analysis of published single-cell RNA sequencing data revealed that CAT1 expression was significantly upregulated in activated HSCs and positively correlated with IL-6 levels. Functional assays demonstrated that IL-6 promotes HSCs proliferation, migration, inflammation, and fibrotic marker expression and inhibited apoptosis, while CAT1 knockdown attenuated these effects. IL-6 overexpression reversed the inhibitory effects of CAT1 knockdown on HSCs activation by regulating JAK2/STAT3 signaling pathway, suggesting that IL-6 acts downstream of CAT1 in promoting fibrosis. In vivo, CAT1 knockdown mitigated liver injury, reduced collagen deposition, and suppressed inflammation in both carbon tetrachloride (CCl₄)-induced hepatic fibrosis and non-alcoholic fatty liver disease (NAFLD) models. However, IL-6 overexpression abolished these protective effects, highlighting the CAT1-IL-6 axis as a crucial regulator of liver fibrosis. These findings suggest that targeting CAT1 may provide a novel therapeutic strategy for hepatic fibrosis by modulating IL-6-mediated inflammatory and fibrogenic pathways.