• Chronic hypobaric hypoxia induces significant shifts in gut microbiota and metabolites, with carnosine levels and Ruminococcus bromii abundance decreasing over 28 days.
• Carnosine inversely correlates with pulmonary arteriole media thickness, suggesting a protective role against vascular remodeling.
• Therapeutic carnosine supplementation restores antioxidant defenses and attenuates vascular remodeling without affecting right ventricular pressures.
• In vitro, carnosine inhibits hypoxia-induced PASMC proliferation and migration, partly via suppression of Nrf2 accumulation, highlighting its potential as a metabolite-based therapy.