ASIC1a promotes liver fibrosis by inhibiting METTL3 SUMOylation

Liver fibrosis represents a major global health burden, with its core pathological feature being the excessive deposition of extracellular matrix driven by activated hepatic stellate cells (HSCs). Acid-sensitive ion channel 1a (ASIC1a) has been shown to be associated with the progression of liver fibrosis, but the molecular mechanisms by which it regulates RNA m⁶A methylation remain unclear. The aim of this study is to investigate the role of ASIC1a in liver fibrosis and the specific regulatory pathways involved. Experiments were conducted using human liver fibrosis tissue, a carbon tetrachloride-induced mouse model of liver fibrosis, and rat hepatic stellate cells; a mouse model with a hepatic stellate cell-specific ASIC1a knockout was generated; performed RIP-qPCR to validate METTL3 binding to target transcripts, while global m⁶A levels were assessed by dot blot and methyltransferase activity assays, the molecular mechanisms were elucidated using methods such as immunoprecipitation, mass spectrometry, SUMOylation assays, and quantitative m⁶A methylation analysis. ASIC1a is significantly up-regulated in fibrotic liver tissue and activated hepatic stellate cells; specific knockout of ASIC1a significantly reduces the severity of liver fibrosis in mice. Mechanistically, ASIC1a binds to SAE1 to inhibit the SUMOylation of METTL3, thereby enhancing its m⁶A methyltransferase activity, which in turn promotes the activation of hepatic stellate cells and the progression of fibrosis. This study has revealed a novel ASIC1a-METTL3-m⁶A de-SUMOylation regulatory axis in the progression of liver fibrosis, suggesting that ASIC1a may serve as a potential target for anti-fibrotic therapy.