Stabilizing MARCH7 as a ferro-guardian against ferroptosis

  • Cell. 2026 Jun 11;189(12):3553-3570.e30. doi: 10.1016/j.cell.2026.03.052.
Wenxiang Huang  1 ,  Ruijun Wang  2 ,  Xinquan Yang  3 ,  Shuangjie Yang  4 ,  Xueliang Yang  2 ,  Gaolu He  5 ,  Songjun Dai  2 ,  Caizhi Li  2 ,  Lianchao Gao  6 ,  Tingting Zhang  2 ,  Peng Zhang  7 ,  Ruihan Chen  5 ,  Keke Zheng  6 ,  Junbing Wu  8 ,  Junxia Min  9 ,  Qian Ba  10 ,  Fudi Wang  11 ,  Qiang Zhang  12
Affiliations
  • 1. Second Affiliated Hospital, Department of Biophysics, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China; National Clinical Research Center of Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2. Second Affiliated Hospital, Department of Biophysics, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China.
  • 3. First Affiliated Hospital, Institute of Translational Medicine, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Hangzhou 310058, China; Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun 130021, China.
  • 4. Second Affiliated Hospital, Department of Biophysics, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China; Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun 130021, China.
  • 5. Department of Orthopedics Surgery, The Second Affiliated Hospital of Medical College, Zhejiang University, Jie Fang Road 88, Hangzhou 310009, China.
  • 6. Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China.
  • 7. First Affiliated Hospital, Institute of Translational Medicine, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 8. Boguan Biotechnologies Co., Ltd., Yantai 264100, Shandong Province, China. Electronic address: [email protected].
  • 9. First Affiliated Hospital, Institute of Translational Medicine, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 10. Science and Technology Innovation Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China. Electronic address: [email protected].
  • 11. Second Affiliated Hospital, Department of Biophysics, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China; Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun 130021, China. Electronic address: [email protected].
  • 12. Second Affiliated Hospital, Department of Biophysics, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China. Electronic address: [email protected].
PMID: 42049018 DOI: 10.1016/j.cell.2026.03.052
Abstract

Ferroptosis is an iron-dependent form of regulated cell death. However, the critical regulators that restrain iron overload to suppress Ferroptosis remain undefined. Utilizing multi-omics, we identify the E3 ubiquitin Ligase membrane-associated RING-CH 7 (MARCH7) as a non-redundant, dual suppressor of Ferroptosis via direct regulation of intracellular iron homeostasis. Mechanistically, MARCH7 ubiquitylates nuclear receptor coactivator 4 (NCOA4) at residue Lys42 by K48-linked ubiquitination, promoting NCOA4 proteasomal degradation and reducing the labile iron pool. Concomitantly, MARCH7 modifies Transferrin Receptor 1 (TFR1) at residue Lys53 by K63 ubiquitination, restricting its plasma membrane translocation and thereby inhibiting cellular iron uptake. Through high-content screening, we further identify emodinanthrone (EmodAn) as a specific MARCH7 stabilizer with a strong cardioprotective effect in rodent models by blocking Ferroptosis. In conclusion, our findings define an iron homeostasis regulatory hub for Ferroptosis and suggest that stabilizing MARCH7 is a promising therapeutic strategy to protect against ferroptosis- or iron-overload-induced diseases.

Keywords
MARCH7; NCOA4; TFR1; ferroptosis; iron overload; myocardial protection; ubiquitination.
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