Enhanced fatty acid availability rewires fibroblasts metabolism and decreases collagen deposition in lung fibrosis.

Pulmonary fibrosis is characterized by irreversible remodeling of the lung parenchyma, which leads to a progressive deterioration in lung function. Pro-fibrotic fibroblasts contribute to uncontrolled extracellular matrix deposition and progression of fibrosis. Emerging evidence implicates metabolic dysregulation - particularly enhanced glycolysis and impaired fatty acid metabolism - in the pathogenesis of pulmonary fibrosis. Here, we investigated whether modulating fatty acid metabolism could counteract fibroblast-driven fibrosis in experimental models. Treatment with pharmacological agents (metformin, rosiglitazone), or genetic ablation of the LPL inhibitory protein, angiopoietin like 4, markedly reduced lung fibrosis and ECM production in bleomycin-induced lung fibrosis mouse model. Similarly, in vitro, provision of albumin-bound fatty acids (FA) in the growth medium reduced TGFβ1-induced collagen production in lung fibroblasts. Mechanistically, excess fatty acid reduced glycolysis, while enhancing mitochondrial function and overall metabolic activity in TGFβ1-treated fibroblasts. This metabolic shift, but not the collagen reduction, was driven by increased fatty acid oxidation via CPT1, as confirmed by the use of the CPT1 inhibitor etomoxir. Importantly, in vivo metabolic interventions downregulated preferentially PDGFRα protein level, while in vitro provision of albumin-bound FA reduced both the amount of collagen produced by αSMA-positive cells and the amount of PDGFRα-positive cells, suggesting a dual role of FA on both pro-fibrotic fibroblasts. Collectively, our findings identify fatty acid oxidation as a potent metabolic checkpoint in fibrotic fibroblasts and support FA availability as a promising strategy to limit lung fibrosis progression.