2. Academic Validation
  3. Huaier Aqueous Extract Combined with Gefitinib Promotes ACSL4-Dependent Ferroptosis and Overcomes Gefitinib Resistance in Non-Small Cell Lung Cancer

Huaier Aqueous Extract Combined with Gefitinib Promotes ACSL4-Dependent Ferroptosis and Overcomes Gefitinib Resistance in Non-Small Cell Lung Cancer

  • Curr Med Sci. 2026 Feb;46(1):197-211. doi: 10.1007/s11596-025-00158-5.
Yi-Heng Du # 1,  Pei Zhang # 2,  Qian-Qian Xue # 1,  Zi-Hao Wang 1,  Xuan Xiang 1,  Yao Liu 1,  Hao-Lei Wang 1,  Qiong Zhou 3
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 2 Department of Respiratory and Critical Care Medicine, Wuhan No. 4 Hospital, Wuhan, 430000, China.
  • 3 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China. [email protected].
  • # Contributed equally.
PMID: 41557244 DOI: 10.1007/s11596-025-00158-5
Abstract

Objective: Huaier, a traditional Chinese medicine (TCM) approved by the National Medical Products Administration (NMPA) of China for Cancer therapy, demonstrates broad antitumor activity. However, its potential to overcome resistance to gefitinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung Cancer (NSCLC) and the underlying mechanisms remain unclear. This study aimed to determine whether Huaier aqueous extract enhances the efficacy of gefitinib against resistant NSCLC and to elucidate the molecular basis of this effect.

Methods: Cell proliferation was evaluated using the Cell Counting Kit-8 and colony formation assays. Apoptosis, Reactive Oxygen Species (ROS), and lipid ROS were measured using flow cytometry, and mitochondrial morphology was examined using transmission electron microscopy. RNA Sequencing and integrated bioinformatics analyses of GEO datasets were performed to identify ferroptosis-related genes, which were validated by qPCR and Western blotting. The in vivo efficacy was assessed using a PC-9GR xenograft model.

Results: Huaier aqueous extract significantly enhanced the sensitivity of gefitinib-resistant NSCLC cells to gefitinib in vitro, and suppressed tumor growth in vivo. Mechanistically, the combined treatment activated the Ferroptosis pathway, accompanied by the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4). Pharmacological inhibition of Ferroptosis or ACSL4 partially attenuated the antitumor effect, confirming their key roles in mediating the synergistic activity of Huaier aqueous extract and gefitinib.

Conclusions: Huaier aqueous extract reversed gefitinib resistance in NSCLC cells by promoting ACSL4-dependent Ferroptosis, thereby providing a promising therapeutic strategy for improving EGFR-TKI efficacy.

Keywords

ACSL4; Ferroptosis; Gefitinib resistance; Huaier; Non-small cell lung cancer (NSCLC); Traditional Chinese Medicine.

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