Methylated GRP94 promotes liver fibrosis progression by enhancing endoplasmic reticulum stress

Liver fibrosis is a crucial and potentially reversible stage in the progression from chronic liver diseases towards liver cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress is closely related to hepatic stellate cell (HSC) activation and liver fibrosis. Liver fibrosis is frequently accompanied by a global increase in hepatic protein methylation. This suggests that there may be potential unexplored connections among ER stress, protein methylation, and liver fibrosis. Here, we identify PRMT1-mediated methylation of the ER chaperone GRP94 at arginine 395 as a critical event that drives HSC activation and liver fibrogenesis. Using proteomic profiling of liver tissues from mouse models induced by carbon tetrachloride (CCl₄) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), combined with studies in human hepatic stellate cells (primary HSCs and the LX2 cell line), we identify that methylation of GRP94 stabilizes the protein by inhibiting its ubiquitination. This modification potentiates the PERK-eIF2α-ATF4 arm of the ER stress response, leading to upregulation of the fibrogenic genes ACTA2 and COL1A1 and promoting HSC activation. Pharmacological inhibition of PRMT1 with MS023 reverses GRP94 methylation, suppresses HSC activation, and attenuates fibrosis progression in both cellular systems and murine models. This finding positions the crosstalk between ER stress and protein arginine methylation as a central node in the pathogenesis of liver fibrosis, suggesting that targeting the methylation of GRP94 may be a potential therapeutic strategy of liver fibrosis.