El kaempferol mitiga la lesión pulmonar inducida por CSE y la ferroptosis epitelial modulando el eje Nrf2/NCOA4/GPx4

Ferroptosis, an iron-dependent regulated necrosis driven by redox imbalance, plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Kaempferol (KF), a bioactive flavonoid from Polygonati Rhizoma, exhibits anti-ferroptotic properties in lipid peroxidation disorders, yet its molecular mechanism against cigarette smoke extract (CSE)-induced ferroptosis in human bronchial epithelial cells (BEAS-2B) remains to be fully elucidated. Using in vitro models of CSE-induced injury, we observed that KF restored cell viability and attenuated cytotoxicity by restoring redox equilibrium-significantly elevating glutathione (GSH) while reducing malondialdehyde (MDA) and labile iron pool (Fe²⁺) levels. Mechanistically, KF suppressed ferritinophagy via nuclear receptor coactivator 4 (NCOA4) inhibition and rescued glutathione peroxidase 4 (GPx4) activity, thereby blocking lipid peroxidation cascades. These effects were mediated through Nrf2-dependent transcriptional activation, counteracting CSE-triggered Nrf2 pathway dysregulation. Our findings reveal that KF mitigates COPD progression by coordinately targeting the Nrf2/NCOA4/GPx4 axis to inhibit ferroptosis, providing a novel therapeutic strategy for oxidative stress-driven pulmonary diseases.