BAIBA attenuates pulmonary fibrosis by modulating the iron/ROS-mitochondrion-apoptosis cascade

Pulmonary fibrosis (PF) is a chronic and progressive lung disease with limited therapeutic options. Beta-aminoisobutyric acid (BAIBA), a muscle-derived metabolite, has been reported to regulate metabolism and oxidative stress, but its potential effects on PF remain unexplored. In this study, we observed that BAIBA treatment significantly improved survival, and alleviated lung fibrosis in bleomycin (BLM)-induced PF mice, comparable to the effects of pirfenidone and metformin. Mechanistically, BAIBA suppressed BLM-induced pulmonary transforming growth factor-β1 (TGF-β1) and β-catenin levels, and the fibrotic phenotypes of fibroblasts. Importantly, BAIBA stabilized iron homeostasis in fibrotic lungs, reduced reactive oxygen species (ROS) production, and preserved mitochondrial structure and function in alveolar epithelial cells, thereby inhibiting apoptosis. Moreover, these protective effects of BAIBA were iron-dependent and required NRF2/HO-1/NQO1 signaling pathways and PGC-1α. Notably, BAIBA also attenuated fibrosis in lipopolysaccharide (LPS)-induced mouse lungs and exhibited minimal effects on normal iron levels or cell proliferation. Collectively, BAIBA exerts potent antifibrotic effects through an iron/ROS-mitochondrion-apoptosis axis. These findings highlight BAIBA as a promising endogenous metabolite-based therapeutic candidate for PF.