Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation

  • Dev Cell. 2025 Apr 18:S1534-5807(25)00206-0. doi: 10.1016/j.devcel.2025.04.004.
Wanxin Guo  1 ,  Congcong Zhang  2 ,  Qianjun Zhou  3 ,  Tianxiang Chen  3 ,  Xin Xu  4 ,  Jianfeng Zhang  3 ,  Xuewen Yu  3 ,  Han Wu  3 ,  Xiao Zhang  4 ,  Lifang Ma  5 ,  Kun Qian  6 ,  Daniel J Klionsky  7 ,  Rui Kang  8 ,  Guido Kroemer  9 ,  Yongchun Yu  10 ,  Daolin Tang  11 ,  Jiayi Wang  12
Affiliations
  • 1. Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 2. Henan University of Chinese Medicine, Zhengzhou 450046, China.
  • 3. Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 4. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 5. Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 6. Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 7. Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
  • 8. Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9. 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.
  • 10. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: [email protected].
  • 11. Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 12. Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Medical Science Laboratory, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
PMID: 40280135 DOI: 10.1016/j.devcel.2025.04.004
Abstract

Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of Ferroptosis. Upon Ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial Reactive Oxygen Species production, thereby stimulating Ferroptosis through lipid peroxidation. A high-fat diet can enhance the Anticancer efficacy of Ferroptosis in lung Cancer mouse models, depending on CCN1. Furthermore, primary lung Cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to Ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based Anticancer therapies.

Keywords
CCN1; cell death; mitochondria.
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