Shen Tianli, Wang Xingjie, Zhang Junxiang, Lin Yuyao, Cai Lindi, Deng Kai, Zhou Cancan, Qiu Guanglin, Lian Jie, Xu Qinhong, Jiang Zhengdong, Zhao Pengwei, Wu Yunhua, Wang Shufeng, Fan Lin, Li Xuqi
Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061 Shaanxi, China.
Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061 Shaanxi, China.
J Adv Res. 2025 Sep 1. doi: 10.1016/j.jare.2025.08.065.
Intestinal ischemia-reperfusion injury (IRI) is a critical condition often requiring emergency intervention. Ferroptosis, a form of regulated cell death driven by phospholipid peroxidation, plays a central role in its pathogenesis.
This study aimed to explore whether CoQ10 could mitigate intestinal IRI by suppressing ferroptosis.
We analyzed serum CoQ10 levels and inflammatory cytokines in patients with mesenteric artery embolism. In mice, intestinal IRI was induced by transient superior mesenteric artery ligation following two weeks of CoQ10 pretreatment. Histology, ELISA, immunoblotting, and RNA sequencing were used to assess therapeutic effects. To explore mechanisms, we used CRISPR/Cas9 to generate FSP1 and COQ2 knockouts in enterocytes, along with targeted metabolomics and co-autoxidation assays. In vivo loss of FSP1 function was induced by AAV9 to evaluate its role in CoQ10-mediated protection.
Utilizing both our own and publicly available intestinal IRI cohorts, we identified a correlation between elevated CoQ10 levels and reduced systemic inflammation, along with decreased oxidized lipid accumulation in ischemia-reperfusion-affected small intestines. Transcriptomic enrichment analyses and biochemical assays demonstrated that CoQ10 supplementation effectively mitigates IRI by modulating lipid metabolism and inhibiting lipid peroxidation and ferroptosis. To elucidate the mechanism of action of CoQ10 against lipid peroxidation and ferroptosis, we established an in vitro ferroptosis-associated intestinal IRI model using enterocytes, which revealed that the CoQ10-mediated suppression of ferroptosis is dependent on FSP1. Targeted metabolomics analyses and co-autoxidation assays indicated that FSP1 suppresses ferroptosis by reducing CoQ10, thereby preventing phospholipid peroxidation. Loss of function FSP1 generated by genetic and pharmacological mechanisms in enterocytes or mouse intestines led to a decrease in the levels of reduced CoQ10, negating the therapeutic effects of CoQ10 on intestinal IRI.
Our study reveals a crucial role of CoQ10 in ferroptosis and highlights the potential of CoQ10 as a promising target for intestinal IRI treatment.
肠道缺血再灌注损伤（IRI）是一种通常需要紧急干预的危急情况。铁死亡是一种由磷脂过氧化驱动的程序性细胞死亡形式，在其发病机制中起核心作用。
本研究旨在探讨辅酶Q10是否可以通过抑制铁死亡来减轻肠道IRI。
我们分析了肠系膜动脉栓塞患者的血清辅酶Q10水平和炎性细胞因子。在小鼠中，在辅酶Q10预处理两周后，通过短暂结扎肠系膜上动脉诱导肠道IRI。采用组织学、酶联免疫吸附测定（ELISA）、免疫印迹和RNA测序来评估治疗效果。为了探究机制，我们使用CRISPR/Cas9在肠细胞中敲除FSP1和COQ2，并进行靶向代谢组学和共自氧化测定。通过腺相关病毒9（AAV9）在体内诱导FSP1功能缺失，以评估其在辅酶Q10介导的保护作用中的作用。
利用我们自己的以及公开可用的肠道IRI队列，我们发现辅酶Q10水平升高与全身炎症减轻以及缺血再灌注影响的小肠中氧化脂质积累减少之间存在相关性。转录组富集分析和生化测定表明，补充辅酶Q10可通过调节脂质代谢、抑制脂质过氧化和铁死亡有效减轻IRI。为了阐明辅酶Q10对抗脂质过氧化和铁死亡的作用机制，我们使用肠细胞建立了体外铁死亡相关的肠道IRI模型，该模型表明辅酶Q10介导的铁死亡抑制依赖于FSP1。靶向代谢组学分析和共自氧化测定表明，FSP1通过还原辅酶Q10来抑制铁死亡，从而防止磷脂过氧化。通过遗传和药理学机制在肠细胞或小鼠肠道中产生的功能缺失型FSP1导致还原型辅酶Q10水平降低，从而消除了辅酶Q10对肠道IRI的治疗作用。
我们的研究揭示了辅酶Q10在铁死亡中的关键作用，并突出了辅酶Q10作为肠道IRI治疗的一个有前景靶点的潜力。
