稳定MARCH7作为抗铁下垂的铁保护剂
Stabilizing MARCH7 as a ferro-guardian against ferroptosis.
摘要(中文译文)
铁死亡是一种铁依赖性的调节性细胞死亡形式。然而，限制铁过载以抑制铁死亡的关键调控因子仍未明确。通过多组学分析，我们鉴定出E3泛素连接酶膜相关RING-CH 7（MARCH7）通过直接调控细胞内铁稳态，作为铁死亡的非冗余双重抑制因子。在机制上，MARCH7通过K48连接的泛素化在赖氨酸42位点对核受体共激活因子4（NCOA4）进行泛素化修饰，促进NCOA4的蛋白酶体降解并减少不稳定铁池。同时，MARCH7通过K63泛素化在赖氨酸53位点修饰转铁蛋白受体1（TFR1），限制其向质膜的转位，从而抑制细胞铁摄取。通过高内涵筛选，我们进一步鉴定出大黄素蒽酮（EmodAn）作为一种特异性MARCH7稳定剂，通过阻断铁死亡在啮齿动物模型中具有强效的心脏保护作用。总之，我们的研究结果定义了一个调控铁死亡的铁稳态调控枢纽，并提示稳定MARCH7是保护机体免受铁死亡或铁过载诱导疾病的一种有前景的治疗策略。
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.
如何引用
AMA
Wenxiang Huang, Ruijun Wang, Xinquan Yang, Shuangjie Yang, Xueliang Yang, Gaolu He, et al. Stabilizing MARCH7 as a ferro-guardian against ferroptosis.. Cell. 2026; doi:10.1016/j.cell.2026.03.052.
APA
Wenxiang Huang, Ruijun Wang, Xinquan Yang, Shuangjie Yang, Xueliang Yang, Gaolu He, et al (2026). Stabilizing MARCH7 as a ferro-guardian against ferroptosis.. Cell. https://doi.org/10.1016/j.cell.2026.03.052
GB/T 7714
Wenxiang Huang, Ruijun Wang, Xinquan Yang, Shuangjie Yang, Xueliang Yang, Gaolu He, et al. Stabilizing MARCH7 as a ferro-guardian against ferroptosis.[J]. Cell, 2026 doi:10.1016/j.cell.2026.03.052.
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