Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review).

Abstract

Tissue fibrosis represents a pathological condition characterized by excessive accumulation of extracellular matrix (ECM) components. Although historically considered a byproduct of glycolysis, lactate has emerged as a key signaling molecule influencing diverse physiological and pathological processes, including fibrosis. Roles have emerged for lactate metabolism and lactylation, a novel post‑translational modification, in regulating fibroblast activation, ECM deposition and fibrotic progression. The present review provides a comprehensive analysis of the current understanding of glycolysis, lactate and lactylation in tissue fibrosis, with emphasis on cardiac, liver, renal and pulmonary fibrosis. The present review examines how enhanced glycolysis supports the energetic and biosynthetic requirements of activated fibroblasts, how lactate functions as a signaling molecule promoting fibrogenesis and how lactylation connects metabolic changes to epigenetic regulation of gene expression. Furthermore, the present review explores potential therapeutic approaches targeting metabolic pathways and lactylation to mitigate fibrosis, while highlighting future directions in this rapidly evolving field.