2. Academic Validation
  3. Stabilizing MARCH7 as a ferro-guardian against ferroptosis

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

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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