放射引起的脑损伤（RBI）是接受颅脑放射治疗的癌症患者面临的主要挑战。然而，RBI 的分子机制和治疗策略仍无定论。随着RBI机制的不断探索，越来越多的研究表明脑血管功能障碍是RBI相关认知障碍的关键因素。由于周细胞是神经血管单位的组成部分，目前的研究对于周细胞在RBI中的具体作用和功能还缺乏了解。我们构建了体内RBI相关认知功能障碍的小鼠模型和体外辐射-诱导周细胞模型，探讨衰老周细胞对血脑屏障和正常中枢神经系统细胞，甚至胶质瘤细胞的影响。为了进一步阐明周细胞自噬对衰老的影响，在动物和细胞水平上探讨了分子机制。最后，我们通过使用衰老药物和全反式视黄酸来验证周细胞衰老的清除，以研究辐射诱导的周细胞衰老的作用。我们的研究结果表明，辐射诱导的周细胞衰老在血脑屏障功能障碍中起着关键作用，导致 RBI 和随后的认知能力下降。引人注目的是，周细胞衰老也有助于神经胶质瘤细胞的生长和侵袭。我们进一步证明，周细胞中的自噬缺陷是周细胞衰老的重要调节机制。此外，雷帕霉素激活的自噬可以逆转周细胞衰老。值得注意的是，通过衰老药物消除衰老细胞可显着减轻辐射引起的认知功能障碍。我们的结果表明，周细胞衰老可能是 RBI 和神经胶质瘤进展的一个有前途的治疗靶标。© 作者 2024。由牛津大学出版社出版代表神经肿瘤学会。

Radiation-induced brain injury (RBI) represents a major challenge for cancer patients undergoing cranial radiotherapy. However, the molecular mechanisms and therapeutic strategies of RBI remain inconclusive. With the continuous exploration of the mechanisms of RBI, an increasing number of studies have implicated cerebrovascular dysfunction as a key factor in RBI-related cognitive impairment. As pericytes are a component of the neurovascular unit, there is still a lack of understanding in current research about the specific role and function of pericytes in RBI.We constructed a mouse model of RBI-associated cognitive dysfunction in vivo and an in vitro radiation-induced pericyte model to explore the effects of senescent pericytes on the blood-brain barrier and normal CNS cells, even glioma cells. To further clarify the effects of pericyte autophagy on senescence, molecular mechanisms were explored at the animal and cellular levels. Finally, we validated the clearance of pericyte senescence by using senolytic drug and all-trans retinoic acid to investigate the role of radiation-induced pericyte senescence.Our findings indicated that radiation-induced pericyte senescence plays a key role in blood-brain barrier dysfunction, leading to RBI and subsequent cognitive decline. Strikingly, pericyte senescence also contributes to the growth and invasion of glioma cells. We further demonstrate that defective autophagy in pericytes is a vital regulatory mechanism for pericyte senescence. Moreover, autophagy activated by rapamycin can reverse pericyte senescence. Notably, the elimination of senescent cells by senolytic drugs significantly mitigated radiation-induced cognitive dysfunction.Our results demonstrated that pericyte senescence may be a promising therapeutic target for RBI and glioma progression.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.