Stabilizing MARCH7 as a ferro-guardian against ferroptosis
Wenxiang Huang, Ruijun Wang, Xinquan Yang, Shuangjie Yang, Xueliang Yang, Gaolu He, Songjun Dai, Caizhi Li, Lianchao Gao, Tingting Zhang, Peng Zhang, Ruihan Chen, Keke Zheng, Junbing Wu, Junxia Min,
Journal：CELL
IF：45.1
DOI：10.1016/j.cell.2026.03.052
PMID：42049018
Published：2026-04-27
research field：分子生物学细胞生物学心血管研究铁代谢泛素-蛋白酶体系统药物发现生物化学
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.
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