Fatty Acid Oxidation-Glycolysis Metabolic Transition Affects ECM Homeostasis in Silica-Induced Pulmonary Fibrosis

Silicosis is a fatal occupational pulmonary disease that is characterized by irreversible replacement of lung parenchyma by aberrant Exracellular matrix (ECM). Metabolic reprogramming is a crucial mechanism for fibrosis. However, how the metabolic rewiring shifts the ECM homeostasis toward overaccumulation remains unclear. Herein, a phenotype with reduction in fatty acid oxidation (FAO) but enhanced glycolysis in myofibroblasts is shown. Perturbation of the glycolytic and FAO pathways, respectively, reveals distinct roles in the metabolic distribution of ECM deposition and degradation. Suppressed glycolysis leads to a decrease in insoluble ECM, primarily due to the inhibition of ECM-modifying enzyme activity and a decrease in glycine synthesis. Notably, promoted FAO facilitates the intracellular degradation pathway of ECM. In addition, the findings revealed that hypoxia-inducible factor-1 alpha (HIF-1α) serves as a crucial metabolic regulator in the transition from FAO to glycolysis, thereby playing a significant role in ECM deposition in silica-induced pulmonary fibrosis. Further, the promotion of FAO, inhibition of glycolysis and HIF-1α reduce ECM production and promote ECM degradation, ultimately impeding the progression of fibrosis and providing therapeutic relief for established pulmonary fibrosis in vivo. These findings unveil the metabolic rewire underpinning the deposition of ECM in silica-induced lung fibrosis and identify novel targets for promoting regression of pulmonary fibrosis.