Abstract
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.