Impaired Lung BCAA Metabolism Promotes Ferroptosis and Resultant Pulmonary Arterial Hypertension-Associated...

Dysregulated branched-chain amino acid (BCAA) metabolism occurs in pulmonary arterial hypertension (PAH), but its role in pulmonary vascular disease and resultant hepatopathy remains undefined. Here, human metabolomic and transcriptomic analyses identified altered BCAA homeostasis and deficits in BCAA catabolic and ferroptosis pathways in PAH pulmonary artery smooth muscle cells (PASMCs). In vitro, excess BCAAs promoted a pro-ferroptotic phenotype in human PASMCs. In monocrotaline-induced PAH, pharmacologic activation of BCAA catabolism with BT2 reduced disease severity, improved right ventricular function, and enhanced exercise capacity while reversing lung ferroptotic signatures and perivascular complement deposition. BT2 also mitigated hepatic shear stress phenotypes, including hepatocyte nuclear expansion and mitochondrial protein dysregulation. Human PAH livers recapitulated many of the hepatic shear stress phenotypes including nuclear expansion and metabolic alterations. These data implicate impaired BCAA metabolism as a driver of PAH via PASMC ferroptosis and potentially link PAH to hepatic metabolic dysfunction through mechanical stress-associated pathways.