Chloride intracellular channel 1 (CLIC1) is a sensor of oxidative stress in endothelial cells (EC). However, the mechanism by which CLIC1 mediate the regulation of endothelial dysfunction has not been established. In this study, overexpressed CLIC1 impaired the ability of the vascular cells to resist oxidative damage and promoted cellular senescence. Besides, suppressed CLIC1 protected against cellular senescence and dysfunction in Human Umbilical Vein Endothelial Cells (HUVECs) through the Nrf2/HO-1 pathway. We also found that ROS-activated CLIC1-induced oxidative stress in HUVECs. Nrf2 nuclear translocation was inhibited by CLIC1 overexpression, but was enhanced by IAA94 (CLICs inhibitor) treatment or knockdown of CLIC1. The Nrf2/HO-1 pathway plays a critical role in the anti-oxidative effect of suppressing CLIC1. And inhibition of CLIC1 decreases oxidative stress injury by downregulating the levels of ROS, MDA, and the expression of EC effectors (ICAM1 and VCAM1) protein expression and promotes the activity of superoxide dismutase (SOD). The AMPK-mediated signaling pathway activates Nrf2 through Nrf2 phosphorylation and nuclear translocation, which is also regulated by CLIC1. Moreover, the activation of CLIC1 contributes to H₂O₂-induced mitochondrial dysfunction and activation of mitochondrial fission. Therefore, elucidation of the mechanisms by which CLIC1 is involved in these pivotal pathways may uncover its therapeutic potential in alleviating ECs oxidative stress and age-related cardiovascular disease development.

氯化物细胞内通道 1 (CLIC1) 是内皮细胞 (EC) 中氧化应激的传感器。然而，CLIC1介导内皮功能障碍调节的机制尚未确定。在这项研究中，过表达的 CLIC1 削弱了血管细胞抵抗氧化损伤的能力并促进了细胞衰老。此外，抑制的 CLIC1 通过 Nrf2/HO-1 通路保护人脐静脉内皮细胞 (HUVEC) 免受细胞衰老和功能障碍。我们还发现 ROS 激活的 CLIC1 诱导 HUVEC 中的氧化应激。Nrf2 核易位被 CLIC1 过表达抑制，但被 IAA94（CLICs 抑制剂）处理或敲除 CLIC1 增强。Nrf2/HO-1 通路在抑制 CLIC1 的抗氧化作用中起关键作用。抑制 CLIC1 通过下调 ROS、MDA 的水平和 EC 效应物（ICAM1 和 VCAM1）蛋白表达的表达来减轻氧化应激损伤，并促进超氧化物歧化酶（SOD）的活性。AMPK 介导的信号通路通过 Nrf2 磷酸化和核易位激活 Nrf2，这也受 CLIC1 调节。此外，CLIC1 的激活有助于 H₂ O ₂诱导的线粒体功能障碍和线粒体裂变的激活。因此，阐明 CLIC1 参与这些关键途径的机制可能会揭示其在减轻 ECs 氧化应激和与年龄相关的心血管疾病发展方面的治疗潜力。