Metabolic reprogramming in fibrosis-related diseases: underlying mechanisms and therapeutics

Fibrosis, which is characterized by excessive extracellular matrix deposition and tissue stiffening, impairs organ function and particularly affects the heart, lungs, liver, and kidneys. The persistent activation of fibrosis-driving cells, such as myofibroblasts, lung epithelial cells, hepatic stellate cells and tubular epithelial cells, by various transcriptional cues and posttranslational modifications (PTMs) rewires cellular substrate metabolism, most notably glucose, amino acid and lipid flux, thereby recapitulating the Warburg effect originally described in cancer cells. Although the organ-specific mechanisms of fibrosis remain incompletely elucidated, different forms of fibrosis share common features of metabolic reprogramming. In this review, we first introduce the core metabolic pathways involved in fibrotic disorders including glycolysis, glutaminolysis and lipid metabolism. Next, we focus on organ-specific metabolic alterations and their regulatory mechanisms in fibrosis-related diseases, including those of the heart, lungs, liver, kidneys, skin, peritoneum and glands, and discuss their underlying mechanisms: altered enzyme expression, subcellular localization and PTMs, within each organ-specific context. In addition to their canonical catalytic functions, enzymes that participate in glucose and lipid metabolism influence fibrosis through nonenzymatic activities mediated by PTMs, including phosphorylation, acetylation, ubiquitination, and the newly recognized lactylation. We further summarize mechanistic insights across organs and metabolic crosstalk in fibrosis. Finally, we discuss the current clinical translation and applications of these pathways. This review provides a reference for further research on metabolic reprogramming, highlights the role of aberrant metabolism and its underlying mechanisms in fibrosis across organs, and identifies emerging therapeutic strategies targeting glycolysis and lipid metabolism.