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Updated: Feb 7, 2026

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Published on: March 20, 2020

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

Qinwen Liu1,2,3, Haojie Chen2, Xiang Li2

  • 1Neurosurgery 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.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 6, 2026
PubMed

Insights

Xanthatin, a natural compound, effectively inhibits triple-negative breast cancer (TNBC) by inducing ferroptosis and mitophagy. It targets CISD1, offering a promising therapeutic strategy for TNBC with minimal toxicity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited therapeutic options and poor patient prognosis.
  • Natural products offer potential avenues for novel cancer therapies.

Purpose of the Study:

  • To identify novel therapeutic agents for TNBC.
  • To elucidate the molecular mechanisms underlying xanthatin's anti-TNBC activity.

Main Methods:

  • Transcriptomic analysis to identify cellular pathways affected by xanthatin.
  • Drug affinity-responsive target stability (DARTS) and mass spectrometry to identify xanthatin's direct binding partner.
  • In vitro assays (Cellular thermal shift assay, surface plasmon resonance, dynamics simulations) to validate target interaction.
  • In vivo studies using an orthotopic TNBC mouse model.

Main Results:

  • Xanthatin inhibits TNBC cell growth and activates ferroptosis, characterized by increased reactive oxygen species (ROS), lipid peroxidation, and iron accumulation, alongside GSH depletion and downregulation of SLC7A11 and GPX4.
  • CDGSH iron-sulfur domain 1 (CISD1) was identified as the direct binding partner of xanthatin, with Tryptophan-75 being the critical residue for interaction.
  • Xanthatin promotes CISD1 ubiquitination and proteasomal degradation, leading to mitochondrial iron homeostasis disruption, ferroptosis, and PINK1/Parkin-dependent mitophagy.
  • Genetic knockdown of CISD1 abrogated xanthatin's anti-cancer effects, confirming CISD1's essential role.
  • Xanthatin suppressed tumor growth in vivo without systemic toxicity.

Conclusions:

  • Xanthatin directly targets CISD1 at the Trp-75 site, inducing a dual ferroptosis-mitophagy mechanism crucial for its anti-TNBC activity.
  • Xanthatin demonstrates significant anti-tumor efficacy and a favorable safety profile in preclinical models.
  • Xanthatin represents a promising therapeutic candidate for TNBC treatment.
Keywords:
CISD1Xanthatinferroptosismitochondrial autophagytriple‐negative breast cancer

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