Nitazoxanide reverses pulmonary vascular remodeling in pulmonary hypertension by targeting the IMPA1-RAGE signaling axis.

Pulmonary hypertension (PH) is a life-threatening disorder characterized by excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling, elevated pulmonary vascular resistance (PVR), and increased pulmonary artery pressure (PAP). These pathological changes ultimately induce right ventricular hypertrophy, right heart failure, and death. Current therapeutic approaches inadequately address the remodeling aspect of PH. Thus, novel therapeutic strategies targeting PASMCs proliferation and vascular remodeling are critically needed. Nitazoxanide, an FDA-approved antiparasitic agent with favorable safety and bioavailability, significantly reduced PAP and alleviated pulmonary vascular remodeling in experimental models of PH, including the SU5416/hypoxia and monocrotaline rat models. Utilizing drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), co-immunoprecipitation and Western blot analysis, we identified inositol monophosphatase 1 (IMPA1) as a novel direct molecular target of nitazoxanide. Mechanistically, nitazoxanide treatment inhibited the IMPA1-RAGE interaction, thereby suppressing downstream activation of the PI3K/Akt/mTOR signaling cascade and attenuating the enhanced glycolysis characteristic of PASMCs in PH. Collectively, our findings highlight nitazoxanide as a promising therapeutic candidate for pulmonary vascular remodeling and pulmonary hypertension.