2. Academic Validation
  3. GPX4-AUTAC induces ferroptosis in breast cancer by promoting the selective autophagic degradation of GPX4 mediated by TRAF6-p62

GPX4-AUTAC induces ferroptosis in breast cancer by promoting the selective autophagic degradation of GPX4 mediated by TRAF6-p62

  • Cell Death Differ. 2025 May 20. doi: 10.1038/s41418-025-01528-1.
Rong Gong # 1 2,  Xiaoya Wan # 1 2,  Shilong Jiang 3,  Yidi Guan 4,  Yizhi Li 1 2,  Ting Jiang 1 2,  Zonglin Chen 5,  Changxin Zhong 1 2,  Linhao He 1 2,  Zhongyuan Xiang 6,  Junya Yang 7,  Biao Xu 7,  Jinming Yang 8,  Yan Cheng 9 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 2 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China.
  • 3 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
  • 4 Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
  • 5 Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 6 Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 7 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 8 Department of Cancer Biology and Toxicology, Department of Pharmacology, College of Medicine and Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
  • 9 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China. yancheng@csu.edu.cn.
  • 10 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China. yancheng@csu.edu.cn.
  • 11 FuRong Laboratory, Changsha, China. yancheng@csu.edu.cn.
  • 12 NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, China. yancheng@csu.edu.cn.
  • 13 Clinical Research Center for Breast Disease in Hunan Province, Changsha, China. yancheng@csu.edu.cn.
  • # Contributed equally.
PMID: 40394165 DOI: 10.1038/s41418-025-01528-1
Abstract

Emerging evidence indicates that activation of Ferroptosis by inhibition of Glutathione Peroxidase 4 (GPX4) may be exploited as a therapeutic strategy to suppress tumor growth and progression. However, application of GPX4 inhibitors in Cancer treatment is hampered by their poor selectivity, which results in unfavorable toxicity. Herein, we identified GPX4 as a candidate for the Autophagy pathway. We showed that GPX4 is ubiquitinated by TNF receptor-associated factor 6 (TRAF6), which promotes its recognition by p62 and leads to its selective autophagic degradation. Utilizing targeted protein degradation (TPD) approach, we developed a GPX4-targeted AUTAC and demonstrated that GPX4-AUTAC promoted the ubiquitination of GPX4, and enhanced the binding with GPX4 and p62, leading to the selective autophagy-dependent degradation of GPX4. Furthermore, GPX4-AUTAC treatment strongly induced Ferroptosis and exhibited potent anti-cancer activity against breast Cancer in vitro, in vivo, and patient-derived organoids (PDOs). Combination treatment of GPX4-AUTAC with sulfasalazine, a ferroptotic inducer, or chemotherapy drugs showed a synergistic anti-cancer effect against breast Cancer. These results uncover a new targeted degradation strategy for GPX4 by inducing selective Autophagy and provide a rationale for the use of GPX4-AUTAC as a novel therapeutic approach to treatment of breast Cancer.

Figures
Products