Mitochondrial fission factor senses and governs ferroptosis

  • Nature. 2026 Oct;658(8137):1036-1046. doi: 10.1038/s41586-026-11020-6.
Songjun Dai  #  1 ,  Xiaoyan Dai  #  2 ,  Tingting Zhang  #  1 ,  Yuanyuan Qi  #  1 ,  Xinquan Yang  #  1  3 ,  Pengfei Diao  1 ,  Chaodong Ge  1  3 ,  Wenxiang Huang  1 ,  Jisheng Ran  1  4 ,  Xueliang Yang  1 ,  Peng Zhang  1 ,  Keke Zheng  2 ,  Ruijun Wang  1 ,  Hong Qian  2 ,  Kunxiao Zhang  5 ,  Junbing Wu  6 ,  Caiyun Fu  7 ,  Qian Ba  8 ,  Junxia Min  9 ,  Fudi Wang  10  11 ,  Qiang Zhang  12
Affiliations
  • 1. The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, The Second Affiliated Hospital, Department of Orthopedic Surgery, State Key Laboratory of Experimental Hematology, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Zhejiang Provincial Key Laboratory of Drug Discovery and Development for Metabolic Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
  • 3. Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun, China.
  • 4. Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou, China.
  • 5. Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
  • 6. Boguan Biotechnologies, Yantai, China.
  • 7. Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Zhejiang Provincial Key Laboratory of Drug Discovery and Development for Metabolic Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China. [email protected].
  • 8. Science and Technology Innovation Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [email protected].
  • 9. The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, The Second Affiliated Hospital, Department of Orthopedic Surgery, State Key Laboratory of Experimental Hematology, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 10. The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, The Second Affiliated Hospital, Department of Orthopedic Surgery, State Key Laboratory of Experimental Hematology, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 11. Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun, China. [email protected].
  • 12. The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, The Second Affiliated Hospital, Department of Orthopedic Surgery, State Key Laboratory of Experimental Hematology, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 42749797 DOI: 10.1038/s41586-026-11020-6
Abstract

Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation and is implicated in diverse pathological states1-4. Although mitochondria and other organelles are increasingly being recognized as important modulators of Ferroptosis5-7, a unifying mechanism that couples organelle dynamics to ferroptotic execution has remained elusive. Here using quantitative phosphoproteomics, we identified mitochondrial fission factor (MFF) as a key ferroptosis-selective regulator. Mechanistically, the lipid mediator 17-HETE promotes phosphorylation of MFF at Ser155, which triggers the coordinated fragmentation and dysfunction of mitochondria and peroxisomes. This remodelling intensifies interorganelle crosstalk, amplifies oxidative stress and accelerates ferroptotic death. To monitor this phosphorylation event in living cells, we developed MFF-SPARK, a phase-separation-based biosensor, for real-time tracking of Ferroptosis through MFF activation. Using MFF-SPARK, we identified PKCβ and DUSP22 as a coordinated kinase-phosphatase pair that governs MFF phosphorylation. We also discovered avermectin B1 as a pharmacological activator of the PKCβ-MFF axis, which can sensitize tumours to Ferroptosis in vivo. Together, our findings establish MFF phosphorylation as a central regulatory node in ferroptosis-associated organelle remodelling and provide a conceptual framework and toolbox for monitoring and pharmacologically interrogating Ferroptosis.

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