The bile acid-oxysterol axis in pulmonary arterial hypertension: from sterol trafficking to precision phenotyping and therapeutic opportunities.

Pulmonary arterial hypertension (PAH) is increasingly recognized as a metabolically dysregulated and inflammatory vascular disease rather than a purely haemodynamic disorder. Among emerging metabolic pathways, the bile acid-oxysterol axis has gained attention as a potential link between sterol imbalance, endothelial dysfunction, and pulmonary vascular remodeling. This narrative review examines current evidence linking selected bile acid and oxysterol species to PAH phenotypes and discusses their potential mechanistic and translational implications. Human lung tissue studies, circulating metabolomics, and experimental models suggest that selected bile acid intermediates and oxysterol species may carry biological information beyond nonspecific disease severity, although their effects are molecule-specific, receptor-specific, and context-dependent rather than uniform across the entire metabolite class. In particular, recent work implicates disturbed lysosomal sterol trafficking and impaired endothelial lysosomal acidification, including NCOA7-related mechanisms, in generating pro-inflammatory sterol signatures that promote endothelial immunoactivation and worsen experimental PAH. At the same time, the biological origin and interpretation of these metabolites are likely heterogeneous, involving lung-intrinsic sterol remodeling, systemic gut-liver signals, and potential confounding from right-heart failure or congestive hepatopathy. We argue that the bile acid-oxysterol axis should not be viewed as uniformly causal or purely biomarker-like across all patients, but rather as a compartment- and endotype-dependent framework whose interpretation depends on the level of evidence considered. This framework has important implications for biomarker development, therapeutic targeting, and precision trial design, and identifies sterol trafficking and lysosomal homeostasis as promising areas for future investigation.