Glycolytic Enzymes as Drivers of Tissue Fibrosis: Metabolic Reprogramming, Lactate Signaling, and Fibrotic Niche Formation

Abstract

Fibrosis is a common pathological consequence of chronic tissue injury, characterized by persistent fibroblast activation, excessive extracellular matrix (ECM) accumulation, and progressive impairment of organ function. Although classical fibrogenic pathways, particularly transforming growth factor-β (TGF-β) signaling, have been extensively studied, growing evidence suggests that metabolic adaptation is an essential component that supports the persistence of the fibrotic phenotype. Among metabolic pathways, enhanced glycolytic activity can support fibrotic remodeling in specific cellular contexts while also participating in adaptive or reparative responses depending on cell identity and disease stage. The glycolysis-lactate-lactylation axis links metabolic alterations with transcriptional reprogramming, immune regulation, and extracellular matrix remodeling. This review summarizes the roles of key glycolytic regulators, including GLUT1, HK2, PFKFB3, PFKM/PFKP, PKM2, LDHA, MCT1/4, and PDK1, across pulmonary, hepatic, renal, cardiac, and cutaneous fibrosis. We further discuss the interactions among glycolytic metabolism, TGF-β signaling, HIF-1α activation, YAP/TAZ-mediated mechanotransduction, and immune-metabolic communication, highlighting emerging therapeutic strategies and challenges in targeting metabolic vulnerabilities in fibrosis.

Keywords

Tissue fibrosis / Glycolytic reprogramming / Lactate metabolism / Histone lactylation / Fibrotic niche / Fibroblast activation / Myofibroblast differentiation / HK2 / PFKFB3 / PKM2 / LDHA

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