Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.
Mol Neurobiol. 2024 Apr;61(4):2151-2164. doi: 10.1007/s12035-023-03685-1. Epub 2023 Oct 20.
Abnormal accumulation of senescent cells in tissues has been shown to facilitate the onset and progression of various diseases. As an important protein involving in the regulation of cellular senescence process, researches suggested GRSF1 as a potential senolytic target to improve multiple physiological and pathological processes. However, the underlying mechanism of cellular senescence on cerebral ischemia-reperfusion injury (CIRI) has not been revealed. Here, we investigated the effect of GRSF1 on CIRI and delved into its specific mechanisms. In the present study, we established a mouse model of cerebral ischemia-reperfusion (CIR) and observed low expression of anti-aging factor GRSF1, along with greatly increased levels of senescence-related markers p16 and p21 and senescence-associated secretory phenotype TNF-α. Furthermore, we found that the expression of GPX4 was elevated parallel to GRSF1 in CIR mice with overexpression of GRSF1, oxidative stress, and iron metabolism-related proteins were inhibited. Functionally, overexpressing GRSF1 significantly ameliorated infarct volume and neurological function scores and suppressed apoptosis in CIR mice, while administration of GPX4 inhibitors reversed these beneficial phenotypes. Taken together, our results indicate cellular senescence as an important pathological mechanism to exacerbate cerebral injury during CIRI, while GRSF1 could inhibit oxidative stress-mediated ferroptosis through upregulating GPX4 to attenuate reperfusion injury, which makes senolytic treatment, especially GRSF1, a promising therapeutic target for CIRI.
衰老细胞在组织中的异常积累已被证明会促进各种疾病的发生和发展。作为一种重要的蛋白质，它参与细胞衰老过程的调节，研究表明 GRSF1 是一种潜在的促衰老靶点，可以改善多种生理和病理过程。然而，细胞衰老对脑缺血再灌注损伤（CIRI）的潜在机制尚未被揭示。在这里，我们研究了 GRSF1 对 CIRI 的影响，并深入探讨了其具体机制。在本研究中，我们建立了脑缺血再灌注（CIR）小鼠模型，并观察到抗老化因子 GRSF1 表达降低，同时衰老相关标志物 p16 和 p21 以及衰老相关分泌表型 TNF-α水平显著升高。此外，我们发现，在过表达 GRSF1 的 CIR 小鼠中，GPX4 的表达与 GRSF1 平行升高，氧化应激和铁代谢相关蛋白受到抑制。功能上，过表达 GRSF1 可显著减轻 CIR 小鼠的梗死体积和神经功能评分，并抑制细胞凋亡，而 GPX4 抑制剂的给药则逆转了这些有益表型。综上所述，我们的结果表明，细胞衰老作为一种重要的病理机制，会加重 CIRI 期间的脑损伤，而 GRSF1 可以通过上调 GPX4 抑制氧化应激介导的铁死亡，从而减轻再灌注损伤，这使得促衰老治疗，特别是 GRSF1，成为 CIRI 的一个有前途的治疗靶点。
