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. Propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aimed to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. It 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, induced a profibrotic phenotype and activated co-cultured fibroblasts in A549 cells. 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-ß/Smad pathway. Overall, these 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-ß/Smad signaling pathway.

TRIOBP modulates ß-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial-mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of ß-catenin. We concluded that the miR-29b‒TRIOBP-TRIO-ß-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.