2. Academic Validation
  3. Anlotinib induced ferroptosis through the p53/xCT/GPX4 pathway in non-small cell lung cancer

Anlotinib induced ferroptosis through the p53/xCT/GPX4 pathway in non-small cell lung cancer

  • Transl Oncol. 2025 Mar:53:102289. doi: 10.1016/j.tranon.2025.102289.
Zhansheng Jiang 1,  Xinge Sun 2,  Yuan Li 3,  Jiahe Wang 3,  Cong Wang 2,  Zhanyu Pan 2,  Yinli Yang 4
Affiliations

Affiliations

  • 1 Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin China. Electronic address: zhjiang@tmu.edu.cn.
  • 2 Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin China.
  • 3 Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 4 Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin China. Electronic address: yylyangyinli@163.com.
PMID: 39827731 DOI: 10.1016/j.tranon.2025.102289
Abstract

Anlotinib, an anti-angiogenic agent, has demonstrated significant anti-tumor effects in non-small cell lung Cancer (NSCLC). However, whether anlotinib exerts its anti-tumor activity in NSCLC through Ferroptosis, and its underlying mechanisms, remain unclear. This study revealed that anlotinib effectively inhibited the proliferation of NSCLC cells in a time- and dose-dependent manner. Treatment with anlotinib resulted in increased levels of Ferroptosis targets (lipid Reactive Oxygen Species and malondialdehyde) and p53 protein expression, while decreasing glutathione levels and the protein expression of solute carrier family 7 member 11 (xCT) and Glutathione Peroxidase 4 (GPX4). Notably, the Ferroptosis inhibitor, Ferrostatin-1 (Fer-1), or the p53 inhibitor, Pifithrin-α (PFT-α), reversed the observed effects on Ferroptosis induction in NSCLC cells. Consistently, our in vivo studies showed accelerated tumor growth rates for the anlotinib/Fer-1 group and the anlotinib/PFT-α group compared with administration of anlotinib alone. However, anlotinib-induced Ferroptosis was suppressed in p53-deficient cells. Collectively, these findings confirm that anlotinib exerts potent anti-tumor effects both in vitro and in vivo by inducing Ferroptosis by modulating the p53/xCT/GPX4 pathway specifically within NSCLC cells.

Keywords

Anlotinib; Anti-angiogenesis; Ferroptosis; NSCLC; p53/xCT/GPX4 pathway.

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