Stabilizing MARCH7 as a ferro-guardian against ferroptosis.

作者：Wenxiang Huang, Ruijun Wang, Xinquan Yang, Shuangjie Yang, Xueliang Yang, Gaolu He, Song-Jun Dai, Caizhi Li, Lianchao Gao, Tingting Zhang, Peng Zhang, Ruihan Chen, Keke Zheng, Jun-bing Wu, Junxia Min, Qiang Ba, Fudi Wang, Qiang Zhang · 发表于：Cell · 年份：2026 · DOI：10.1016/j.cell.2026.03.052 · 被引用次数：10 · 研究领域：Medicine

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.