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β-Sitosterol attenuates pulmonary arterial hypertension by activating the Nrf2–GPX4 axis to inhibit ferroptosis in pulmonary vascular cells
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DOI：10.1016/j.bcp.2026.118306.png)
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Abstract
En 中文
Pulmonary arterial hypertension (PAH) is a progressive vascular disorder in which oxidative stress and ferroptosis are key pathogenic drivers. Although β-sitosterol (BS) shows therapeutic potential in PAH; however, its link to ferroptosis modulation remain poorly elucidated. This study evaluated the anti‑PAH efficacy of BS and its underlying mechanisms, focusing on the Nrf2–GPX4 axis, using a monocrotaline (MCT)‑induced rat model and hypoxia‑induced pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (PASMCs). Inflammation responses, reactive oxygen species (ROS), and ferroptosis-related markers were assessed, along with molecular docking and pharmacological inhibition. In vivo, BS significantly ameliorated pulmonary vascular remodeling, improved right ventricular function, and mitigated oxidative stress by reducing ROS and MDA while restoring GSH levels, while up regulating the ferroptosis-protecive proteins xCT and GPX4. Molecular docking suggested direct interaction between BS and Nrf2. Notably, immunofluorescence revealed Nrf2 localization in both CD31+ endothelial and α‑SMA+ smooth muscle cells, with BS treatment substantially enhancing Nrf2 accumulation in both lineages. In vitro, BS promoted Nrf2 nuclear translocation in hypoxia-induced PAECs and PASMCs, correlating with suppressed oxidative and inflammatory responses and elevated xCT and GPX4 expression. Notably, the anti-oxidative and anti-ferroptotic effects of BS were abolished by the Nrf2 inhibitor ML385. These findings demonstrate that BS attenuates PAH via Nrf2‑GPX4‑driven ferroptosis inhibition in both in PAECs and PASMCs, uncovering a novel therapeutic target and new research directions regarding PAH pathogenesis and treatment.
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