PRPF19 drives hepatic stellate cell activation and liver fibrosis via PKM2-mediated glycolytic reprogramming

Activation of hepatic stellate cells (HSCs) is a pivotal event driving fibrogenic remodeling of the injured liver. However, the upstream regulators that integrate post-translational signaling with metabolic reprogramming during HSC activation remain poorly defined. Here, we identify pre-mRNA processing factor 19 (PRPF19) as a ubiquitination-linked metabolic regulator that promotes HSC activation. PRPF19 expression was elevated in human and murine fibrotic livers, enriched in activated HSCs, and positively correlated with fibrosis severity. Conditional deletion of Prpf19 in HSCs (Prpf19flox/flox;Lrat-CreERT2), but not in hepatocytes (Prpf19flox/flox;Alb-CreERT2), attenuated HSC activation and liver fibrosis in vivo. Integrated transcriptomic, proteomic, and metabolomic analyses indicated that PRPF19 sustains glycolytic flux and transcriptional programs associated with HSC activation. Mechanistically, PRPF19 promoted K63-linked ubiquitination of pyruvate kinase M2 (PKM2), facilitating its nuclear translocation and hypoxia-inducible factor 1α (HIF-1α)-dependent transcription of glycolytic and fibrogenic genes. These findings support a role for the PRPF19-PKM2 pathway in metabolic regulation during HSC activation and liver fibrosis. Zhang et al. show that PRPF19 promotes hepatic stellate cell activation and liver fibrosis by driving PKM2-dependent glycolytic reprogramming, identifying a potential metabolic target in chronic liver disease.