Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation

Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a novel metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes A+B, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared to a traditional carnitine palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for the mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only uncover a previously unrecognized metabolic role of mitochondrial CCN1, but also establish a potential strategy for enhancing ferroptosis-based anticancer therapies.

铁死亡（Ferroptosis）是一种氧化性细胞死亡形式，但其关键代谢过程仍未完全阐明。我们采用全面多组学筛选策略，鉴定出细胞通讯网络因子1（CCN1）为铁死亡的新型代谢催化剂。在铁死亡诱导后，CCN1会转位至线粒体复合物A+B，促进依赖于电子转移黄素蛋白α亚基（ETFA）的脂肪酸β氧化过程。相较于传统的肉碱棕榈酰转移酶2（CPT2）-ETFA通路，CCN1-ETFA通路可为线粒体活性氧生成提供额外底物，进而通过脂质过氧化刺激铁死亡。高脂饮食可增强肺癌小鼠模型中铁死亡的抗癌功效，且该效应依赖于CCN1。此外，源自高甘油三酯血症患者或CCN1高表达患者的原代肺癌细胞，在体外与体内实验中均表现出对铁死亡更高的敏感性。本研究不仅揭示了线粒体CCN1此前未被认知的代谢功能，同时确立了一种增强基于铁死亡的抗癌治疗策略的潜在途径。