2. Academic Validation
  3. Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression

Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression

  • Mol Cell. 2025 Dec 18;85(24):4602-4620.e9. doi: 10.1016/j.molcel.2025.11.023.
Yameng Hu 1,  Ziwen Li 2,  Man Li 2,  Xingui Wu 3,  Shuxia Zhang 2,  Miaoling Tang 2,  Ruyuan Yu 2,  Meisongzhu Yang 2,  Xin Chen 3,  Libing Song 4,  Guido Kroemer 5,  Valerian E Kagan 6,  Hülya Bayir 7,  Rui Kang 8,  Jinbao Liu 9,  Daolin Tang 10,  Jun Li 11
Affiliations

Affiliations

  • 1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Diseases, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 3 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Diseases, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 5 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.
  • 6 Department of Environmental Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Department of Pediatrics, Columbia University, New York, NY, USA.
  • 8 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
  • 9 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Diseases, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China. Electronic address: [email protected].
  • 10 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected].
  • 11 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 41418756 DOI: 10.1016/j.molcel.2025.11.023
Abstract

Inducing lipid peroxidation-dependent Ferroptosis is a promising Anticancer strategy; however, the development of resistance poses a considerable challenge. This study identifies peroxiredoxin 6 (PRDX6) as a crucial modulator of Glutathione Peroxidase 4 (GPX4), affecting its localization and functional roles, thus contributing to Ferroptosis resistance. PRDX6, endowed with Phospholipase A2 activity, catalyzes the conversion of peroxy-phospholipids to lysophospholipids and oxidized fatty acids. Through targeted structural mutations and biochemical analyses, we demonstrate that PRDX6 binds to GPX4 via a C47 disulfide bond, facilitating GPX4's membrane translocation and enhanced production of hydroxy fatty acids. Combining the inhibition of PRDX6 with Ferroptosis inducers increases lipid peroxidation, effectively suppressing tumor growth in liver and ovarian Cancer mouse models, including patient-derived models. Furthermore, high PRDX6 expression correlates with shorter progression-free survival across multiple human Cancer types. Collectively, our findings delineate a PRDX6-dependent mechanism in Ferroptosis defense, offering new perspectives for targeted Cancer therapy.

Keywords

PRDX6; cancer therapy; lysophospholipids; membrane translocation of GPX4.

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