Vitexin ameliorates PM2.5-triggered pulmonary toxicity through dual modulation of endoplasmic reticulum stress and ferroptosis pathways

Fine particulate matter (PM2.5) primarily damages the respiratory system, leading to lung injury with limited therapeutic options. Recent studies suggest that ferroptosis and endoplasmic reticulum stress (ERS) play pivotal roles in PM2.5-induced pulmonary injury. This integrated study, combining in vivo and in vitro approaches, evaluated the protective potential of Vitexin (VI), a natural flavonoid, against PM2.5-mediated lung injury, focusing on its mechanisms involving ERS and ferroptosis. For the in vivo arm, PM2.5-exposed mice received VI (15-60 mg/kg) or dexamethasone (0.125 mg/kg) via oral gavage over 8 weeks, with systemic biospecimen collection (serum/BALF/lung) post-euthanasia at endpoint. Concurrently, in vitro, BEAS-2B cells were pretreated with 30 μM VI and then exposed to PM2.5 supernatant (400 μg/mL) for 24 h, with cellular responses evaluated after standardized culture and viability assessment via CCK-8 assay. Meanwhile, we employed molecular simulations, which predicted a high-affinity binding between VI and GPX4, suggesting direct stabilization. Experimental investigations elucidated that VI alleviates PM2.5-triggered ferroptosis through a dual-pathway synergy: it activates the NRF2/HO-1/NQO1 pathway to enhance antioxidant capacity, while suppressing endoplasmic reticulum stress via the PERK/eIF2α/ATF4/CHOP axis. The attenuation of ERS, in turn, upregulates system Xc^－ activity and GPX4 expression. These integrated actions collectively reduce lipid peroxidation and attenuate ferroptotic cell death. In summary, VI significantly exerted a protective effect against PM2.5-induced lung injury by inhibiting ERS-mediated ferroptosis, highlighting its promise as a protective agent against air pollution-related pulmonary damage.