# Kaempferol Mitigates CSE‐Induced Lung Injury and Epithelial Cell Ferroptosis via Modulating Nrf2/NCOA4/GPx4 Axis

## TL;DR

Kaempferol helps protect lung cells from cigarette smoke damage by preventing a type of cell death called ferroptosis through a specific molecular pathway.

## Contribution

Kaempferol's anti-ferroptotic mechanism via the Nrf2/NCOA4/GPx4 axis in CSE-induced lung injury is newly elucidated.

## Key findings

- Kaempferol restored cell viability and redox balance by increasing GSH and reducing MDA and Fe2+ levels.
- KF inhibited ferritinophagy through NCOA4 suppression and rescued GPx4 activity to block lipid peroxidation.
- Nrf2-dependent transcriptional activation mediated KF's protective effects against CSE-induced ferroptosis.

## Abstract

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.