Defective branched-chain amino acid catabolism promotes pulmonary fibrosis by inducing apoptosis resistance of myofibroblasts in mice

Pulmonary fibrosis (PF) is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Branched-chain amino acids (BCAAs) are a group of essential amino acids consisting of valine, leucine, and isoleucine. BCAAs can be converted into intermediate products, branched-chain α-keto acids (BCKAs), which undergo irreversible decarboxylation and dehydrogenation reactions under the action of the branched-chain α-keto acid dehydrogenase complex (BCKDH). Although evidence suggests that the deficiency of BCAA catabolism contributes to tumor and heart failure, the contribution of BCAA metabolism regulation to PF remains largely elusive. Mouse PF models were induced by bleomycin (BLM). We first evaluated the changes in BCAA metabolism in the lungs of PF mice. Subsequently, BCAA metabolic regulation was achieved through exogenous BCAA supplementation, BCKDK inhibitor BT2, or adenovirus-mediated overexpression of PP2Cm (Ad-PP2Cm). We evaluated whether BCAA metabolic defects induce apoptosis resistance in myofibroblasts through the mTORC1/p70S6K/BAD axis, thereby promoting the progression of pulmonary fibrosis via histopathological, biochemical, and molecular biological assessments. We found that, in the lungs of BLM-induced PF mice, the expression and activity of BCAA metabolic enzymes are inhibited, accompanied by the accumulation of BCAAs and BCKAs in the lungs. Supplementation of BCAA promoted the development of PF. Conversely, enhancing BCAA catabolism by inhibiting BCKDK or overexpressing PP2Cm to activate BCKDH suppressed PF progression in mice. Mechanistically, the deficiency of BCAA catabolism facilitated myofibroblast accumulation by conferring resistance to apoptosis. Furthermore, mTORC1/p70S6K/BAD was found to be the key upstream regulator of BCAA catabolism defect-induced apoptosis resistance in myofibroblasts. Our study reveals that defective BCAA catabolism significantly promotes the progression of PF by inducing apoptosis resistance in myofibroblasts. Therefore, targeting this pathway may be a promising therapeutic strategy for PF.