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

Background: Dysregulated branched chain amino acid (BCAA) homeostasis occurs in pulmonary arterial hypertension (PAH) as BCAA metabolites accumulate and cause metabolic alterations in pulmonary artery smooth muscle cells (PASMC). In other cells, altered BCAA metabolism promotes ferroptosis, a PAH-inducing metabolic pathway. However, the interplay between BCAAs, lung ferroptosis, and PAH is unexplored, as is the impact of PAH severity on liver molecular regulation, a key unknown as recent clinical data highlight the importance of the lung-right heart-liver axis in PAH outcomes. Methods: Human metabolomic and transcriptomic studies examined BCAA metabolism and ferroptosis pathways. The relationship between BCAAs and ferroptotic-phenotypes in PASMCs was evaluated. Multi-omics and physiological analyses evaluated how modulation of BCAA catabolism impacted preclinical PAH multi-organ physiology. Confocal microscopy and proteomic analyses assessed hepatic alterations in human PAH. Results: , excess BCAAs induced mitochondrial fragmentation, reactive oxygen species generation, and lipid peroxidation in PASMC. Moreover, BCAAs promoted PASMC death, which ferrostatin-1, a ferroptosis antagonist, rescued. BT2, a small-molecule inducer of BCAA catabolism, reduced PAH severity, improved RV function, and enhanced maximal exercise capacity in monocrotaline rats. BT2 blunted pro-ferroptotic changes in lung metabolites and proteins, and combatted peri-vascular complement deposition. In the liver, BT2 blocked mechanical shear stress phenotypes including hepatocyte nuclear expansion and restructured mitochondrial protein regulation and the metabolomic signature. Additionally, a low BCAA diet modestly combatted preclinical PAH severity. Finally, human PAH livers exhibited increased hepatocyte nuclear size and derangements in liver metabolic regulation. Conclusions: Impaired BCAA metabolism promotes PAH via ferroptosis. PAH severity is associated with hepatic pathological shear stress phenotypes and metabolic alterations, which are combatted by a BCAA-targeted therapy.