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.