Glycolytic Metabolic Reprogramming and Epigenetic Crosstalk in Pulmonary Fibrosis

Abstract

: Pulmonary fibrosis is a chronic, progressive, and fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible parenchymal destruction, with idiopathic pulmonary fibrosis (IPF) as its most typical and lethal subtype. IPF confers an extremely poor prognosis, with a median survival of only 2–3 years after diagnosis and no curative therapies available to date. Mounting evidence has validated that the bidirectional crosstalk between glycolytic metabolic reprogramming and epigenetic modifications acts as a core mechanism sustaining the activated phenotype of pulmonary myofibroblasts and reinforcing the pathological progression of pulmonary fibrosis. This review summarizes the signature features of hyperactive glycolysis in pulmonary myofibroblasts, with a focus on the direct regulatory effects of glycolysis-derived metabolites on epigenetic programming: nuclear acetyl-CoA accumulation provides abundant substrates for histone acetylation; an imbalanced NAD⁺/NADH ratio suppresses the catalytic activity of Sirtuin family deacetylases; lactate overload induces novel histone lactylation modifications that modulate gene transcription; and α - ketoglutarate depletion and competitive inhibition dampen DNA/histone demethylase activity. Furthermore, we discuss the reverse reinforcing effect of epigenetic remodeling on the persistent expression of glycolysis-related genes, highlighting a reciprocal positive feedback loop between metabolic and epigenetic alterations. This crosstalk network offers a critical theoretical basis and actionable targets for disrupting the pathological homeostasis of fibrosis and developing novel anti-fibrotic interventions