2. Academic Validation
  3. Kaempferol Mitigates CSE-Induced Lung Injury and Epithelial Cell Ferroptosis via Modulating Nrf2/NCOA4/GPx4 Axis

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

  • J Cell Mol Med. 2026 Jan;30(1):e71010. doi: 10.1111/jcmm.71010.
Fengri Jin 1,  Yanfei Xing 2,  Songyu Li 3,  Zhennan Yi 4,  Aibin Wu 1,  Xin Li 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.
  • 2 Department of Ophthalmology, Zhaoqing Medical College, Zhaoqing, Guangdong, People's Republic of China.
  • 3 Department of Zhanjiang Institute of Clinical Medicine, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, People's Republic of China.
  • 4 Department of Respiratory Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.
PMID: 41474210 DOI: 10.1111/jcmm.71010
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.

Keywords

COPD; ferritinophagy; ferroptosis; flavonoids; kaempferol.

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