Aging-Associated Metabolite Methylmalonic Acid Increases Susceptibility to Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Previous studies have indicated that propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aims to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. The present study revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized by an increase in propionyl-CoA carboxylase and methylmalonyl-CoA epimerase expression, and a decrease in methylmalonyl-CoA mutase expression. Knockdown of methylmalonyl-CoA mutase, the key enzyme in propionate metabolism, in A549 cells induced a profibrotic phenotype and activated co-cultured fibroblasts. MMA exacerbated bleomycin-induced mouse lung fibrosis and induced a profibrotic phenotype in both epithelial cells and fibroblasts through activation of the canonical transforming growth factor-β/Smad pathway. Overall, our findings unveil an alteration of propionate metabolism in IPF, leading to MMA accumulation, thus exacerbating lung fibrosis through promoting profibrotic phenotypic transitions via the canonical transforming growth factor-β/Smad signaling pathway.