PRC1 promotes MAFLD progression by regulating glycolysis/lactylation axis and forming a positive feedback loop.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a globally prevalent liver disorder with rising incidence, carries significant risks of progression to end-stage conditions like liver fibrosis and hepatocellular carcinoma. Glycolysis plays important roles as a key metabolic pathway in the MAFLD disease process. Protein regulator of cytokinesis 1 (PRC1) is closely related to the glycolytic pathway and chronic liver diseases. This study investigated the roles of PRC1 in MAFLD pathogenesis, as a critical driver of disease progression. Experimental analyses confirmed that PRC1 was aberrantly overexpressed in MAFLD. In cellular and animal studies, PRC1 overexpression exacerbated hepatic steatosis by promoting triglyceride and total cholesterol accumulation, along with lipid droplet formation. Integrated RNA sequencing and untargeted metabolomics identified glycolysis activation as the key mechanism underlying PRC1-mediated MAFLD progression. Inhibition of glycolysis with 2-DG and Oxamate markedly attenuated steatosis. Mechanistically, PRC1-driven hyperactivation of glycolysis increased histone H4K12 lactylation (H4K12la). Further experimental results showed that H4K12la enrichment at the PRC1 promoter region maintained its expression to promote MAFLD progression. This interaction established a self-reinforcing "PRC1-glycolysis-lactylation" positive feedback loop, perpetuating PRC1 overexpression and accelerating MAFLD progression. Targeting the feedback loop might provide novel therapeutic strategies for MAFLD treatment.