2. Academic Validation
  3. Xanthatin Targets CISD1 to Drive Ferroptosis and Mitophagy as a Dual Anticancer Strategy in Triple-Negative Breast Cancer

Xanthatin Targets CISD1 to Drive Ferroptosis and Mitophagy as a Dual Anticancer Strategy in Triple-Negative Breast Cancer

  • Adv Sci (Weinh). 2026 Apr;13(21):e20051. doi: 10.1002/advs.202520051.
Qinwen Liu 1 2 3,  Haojie Chen 2,  Xiang Li 2,  Jingxin Liu 2,  Yiwen Li 2,  Zhenyi Shi 2,  Shenshen Guo 2,  Qingfeng Du 4 5 6 7,  Aiping Lu 3,  Daogang Guan 2 8
Affiliations

Affiliations

  • 1 Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China.
  • 3 Institute of Systems Medicine and Health Sciences, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China.
  • 4 Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine For Qingzhi Diseases, Guangzhou, P. R. China.
  • 5 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, P. R. China.
  • 6 Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, Guangdong, P. R. China.
  • 7 Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, Guangdong, P. R. China.
  • 8 Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, P. R. China.
PMID: 41646014 DOI: 10.1002/advs.202520051
Abstract

Triple-negative breast Cancer (TNBC) is an aggressive subtype with poor prognosis. Here, we identify xanthatin, a sesquiterpene lactone from Xanthium species, as a potent inhibitor of TNBC cell growth with minimal toxicity to normal cells. Transcriptomic analyses revealed that xanthatin activates Ferroptosis, evidenced by elevated ROS, lipid peroxidation, and Fe2 + accumulation, together with GSH depletion and downregulation of SLC7A11 and GPX4. Target identification by drug affinity responsive target stability and mass spectrometry uncovered CDGSH iron sulfur domain 1 (CISD1) as the direct binding partner of xanthatin. Cellular thermal shift assay, surface plasmon resonance, and dynamics simulations consistently demonstrated that tryptophan-75 is the critical residue mediating this interaction. Functionally, xanthatin promotes CISD1 ubiquitination and proteasomal degradation, thereby disrupting mitochondrial iron homeostasis and inducing Ferroptosis. CISD1 destabilization further impaired mitochondrial integrity and activated PINK1/Parkin-dependent Mitophagy, establishing a dual ferroptosis-mitophagy mechanism. Importantly, genetic knockdown of CISD1 markedly attenuated the Anticancer activity of xanthatin, confirming its essential role. In an orthotopic TNBC mouse model, xanthatin significantly suppressed tumor growth without causing systemic toxicity. Collectively, our findings provide the first demonstration that xanthatin directly targets CISD1 at the Trp-75 site to trigger Ferroptosis and Mitophagy, highlighting its promise as a therapeutic candidate for TNBC.

Keywords

CISD1; Xanthatin; ferroptosis; mitochondrial autophagy; triple‐negative breast cancer.

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