Irisin attenuates liver fibrosis by regulating energy metabolism and HMGB1/β-catenin signaling in hepatic stellate cells

Abstract

Liver fibrosis is characterized by excessive extracellular matrix accumulation during chronic liver disease progression. Hepatic stellate cell (HSC) activation involves metabolic reprogramming, while both HMGB1 and β-catenin pathways have been implicated in HSC activation and liver fibrosis progression. Given irisin's established role in metabolic regulation and emerging evidence of its anti-fibrotic properties, we investigated its effects on HSC activation and liver fibrosis, focusing on potential metabolic regulation through the HMGB1/β-catenin pathway. Using both in vitro HSC-T6 cell culture and in vivo CCl₄-induced rat liver fibrosis model, we analyzed irisin's impact on HSC metabolism and fibrosis progression. Our results demonstrated that irisin dose-dependently suppressed HSC-T6 cell viability and glycolytic metabolism, significantly reducing ATP levels, glucose consumption, and lactate production at concentrations of 80–100 nmol/L. Irisin treatment markedly inhibited HSC-T6 cell proliferation and migration while inducing cellular senescence, as evidenced by increased H3K9me3, γ-H2AX, P16, and P21 expression. Mechanistically, irisin systematically downregulated key glycolytic enzymes (HK2, PFK1, PKM2, LDHA) and modulated the HMGB1/β-catenin pathway by reducing both cytoplasmic HMGB1 expression and β-catenin nuclear translocation. In the CCl₄-induced rat model, irisin treatment significantly ameliorated liver fibrosis, as evidenced by reduced collagen deposition and α-SMA expression, while improving liver function indicators and decreasing serum fibrosis markers (HA, PIIIP, HMGB1), showing therapeutic effects comparable to colchicine. These findings reveal irisin's anti-fibrotic effects through metabolic regulation and HMGB1/β-catenin pathway modulation, suggesting its potential as a therapeutic agent for liver fibrosis.