Omaveloxolone Driven NRF2 Activation as a Novel Therapeutic Strategy for Pulmonary Hypertension

BACKGROUND: Pulmonary arterial hypertension is a progressive and life-threatening disorder characterized by elevated pulmonary arterial pressure, right ventricular hypertrophy, and eventual right heart failure. Omaveloxolone, an orally bioavailable synthetic triterpenoid recently approved for Friedreich's ataxia, improves mitochondrial bioenergetics and restores redox homeostasis. We investigated whether pharmacological activation of NRF2 (nuclear factor erythroid 2-related factor 2) by Omaveloxolone confers therapeutic benefit in pulmonary hypertension (PH). METHODS: The effects of Omaveloxolone were evaluated in chronic hypoxia-induced PH in mice, monocrotaline-induced PH in rats, and sugen/hypoxia-induced PH in rats, together with studies in human pulmonary artery endothelial and smooth muscle cells. RESULTS: NRF2 expression and nuclear localization were reduced in PH lungs and hypoxia-exposed cells, whereas Omaveloxolone restored NRF2 activity and increased downstream antioxidant enzymes. In endothelial cells, Omaveloxolone reduced oxidative stress, suppressed inflammatory signaling, and inhibited endothelial-to-mesenchymal transition. In smooth muscle cells, it attenuated oxidative stress and normalized abnormal proliferation, migration, and apoptosis. Omaveloxolone reduced HIF (hypoxia-inducible factor)-2α accumulation in endothelial cells and inhibited HIF-1α stabilization in smooth muscle cells. NRF2 knockdown attenuated these effects, supporting pathway dependency. Omaveloxolone attenuated PH, reduced right ventricular hypertrophy and vascular remodeling, and improved right ventricular function across hypoxia, monocrotaline, and sugen/hypoxia models under both preventive and therapeutic regimens. CONCLUSIONS: These findings demonstrate that Omaveloxolone exerts disease-modifying effects in PH by activating NRF2-dependent cytoprotective pathways, reducing oxidative stress, and suppressing inflammation, supporting its translational potential as a therapeutic strategy.