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 cells (HSCs) 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. Therefore, this study aims to deeply elucidate whether and how the methylated modification of the ER stress key regulatory protein GRP94, thereby playing a crucial role in mediating the activation of HSCs and liver fibrosis progression.