浙江大学医学院张强团队近日取得一项新成果。经过不懈努力，他们发现了稳定MARCH7作为铁保护因子抗铁死亡。2026年4月27日出版的《细胞》杂志发表了这项成果。
利用多组学，研究小组发现E3泛素连接酶膜相关环CH7 （MARCH7）通过直接调节细胞内铁稳态作为铁死亡的非冗余双抑制因子。在机制上，MARCH7通过k48连锁泛素化使核受体共激活因子4 （NCOA4）在Lys42残基上泛素化，促进NCOA4蛋白酶体降解，减少不稳定铁池。同时，MARCH7通过K63泛素化修饰Lys53残基上的转铁蛋白受体1 (TFR1)，限制其质膜易位，从而抑制细胞铁摄取。
通过高含量筛选，课题组研究人员进一步确定了Emodinanthrone （EmodAn）是一种特异性的MARCH7稳定剂，通过阻断铁死亡在啮齿动物模型中具有很强的心脏保护作用。总之，他们的研究结果确定了铁中毒的铁稳态调节中心，并表明稳定MARCH7是一种有希望的治疗策略，可以预防铁中毒或铁超载引起的疾病。
研究人员表示，铁死亡是一种依赖铁的细胞死亡形式。然而，抑制铁过载以抑制铁死亡的关键调节因子仍未明确。
附：英文原文
Title: Stabilizing MARCH7 as a ferro-guardian against ferroptosis
Author: 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, Qian Ba, Fudi Wang, Qiang Zhang
Issue&Volume: 2026-04-27
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.
DOI: 10.1016/j.cell.2026.03.052
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00388-0