Metformin Inhibits Cardiac Fibroblast Differentiation by Promoting Fatty Acid β-Oxidation: Implications for Age-Associated Cardiac Fibrosis.

Cardiac fibrosis is a hallmark of pathological cardiac remodeling, characterized by fibroblast activation, excessive extracellular matrix deposition, and myocardial hypertrophy, ultimately leading to cardiac dysfunction. Aging exacerbates these processes through metabolic stress and impaired mitochondrial bioenergetics. Here, we investigated the anti-fibrotic effects of metformin and the role of fatty acid β-oxidation (FAO) in regulating cardiac fibroblast differentiation. Metformin significantly attenuated transforming growth factor-β (TGF-β)-induced cardiac fibroblast activation and the associated senescence(definition)-like phenotype. These effects were accompanied by enhanced FAO and increased mitochondrial oxygen consumption rate (OCR), indicating improved mitochondrial function. Importantly, inhibition of carnitine palmitoyltransferase-1 (CPT1) with etomoxir largely abolished the beneficial effects of metformin on mitochondrial respiration, fibroblast activation, and cellular senescence, demonstrating a critical role for FAO. Mechanistically, metformin increased CPT1 activity and acetyl-CoA levels while reducing malonyl-CoA accumulation, thereby promoting mitochondrial fatty acid utilization. These findings were corroborated in aged Apoe^-/- mice, where metformin reduced the expression of cardiac fibroblast differentiation markers and enhanced FAO-associated markers. Collectively, our findings demonstrate that metformin suppresses cardiac fibroblast differentiation and senescence by preserving mitochondrial bioenergetics through FAO-dependent mechanisms, revealing a metabolic basis for its anti-fibrotic actions and supporting its therapeutic potential in age-related cardiovascular disease.