PGK1 Lactylation-Driven Self-Reinforcing Loop Orchestrates Glycolytic Reprogramming in FSP1(+) Macrophages in Liver Fibrosis.

Liver fibrosis shows limited treatment efficacy, driven by metabolic reprogramming and epigenetics, while the role of lactate-mediated lactylation in hepatic microenvironment remains unclear. Here, through integrative analysis of public databases and human cirrhotic liver tissues, we identified a pathogenic FSP1(+) (fibroblast specific protein 1) macrophage subset as a key therapeutic target. We uncovered a novel FSP1-glycolysis-lactylation axis that drives fibrotic progression through metabolic-immune crosstalk. Expanded FSP1(+) macrophage infiltration was observed in human cirrhotic liver tissues and myeloid-specific Fsp1 knockout markedly attenuates inflammation and fibrosis. Mechanistic investigations reveal that FSP1 physically interacts with pyruvate kinase M2 (PKM2) in macrophages, inhibiting its ubiquitin-proteasome degradation to stabilize the enzyme. This FSP1-PKM2 interaction enhances glycolytic flux and lactate production, which in turn promotes KAT2B-dependent lactylation of phosphoglycerate kinase 1 (PGK1) at lysine 353 (K353). The posttranslational modification creates a positive feedback loop by concurrently activating PGK1 and pyruvate dehydrogenase kinase 1, which blocks mitochondrial pyruvate metabolism, thereby amplifying glycolysis and PGK1 lactylation. Notably, we developed a cell-penetrating peptide targeting PGK1-K353 lactylation that effectively attenuates the progression of liver fibrosis. Our findings establish lactate-mediated lactylation of PGK1 as a critical node in fibrotic metabolism and reveal a previously unrecognized FSP1-glycolysis axis that sustains the pro-fibrotic microenvironment. Targeting PGK1-K353 lactylation represents a promising therapeutic strategy for chronic liver diseases.