复发引起的胶质母细胞瘤在临床上具有 10-15 个月总生存期的挑战。之前我们发现胶质母细胞瘤中的治疗诱导衰老（TIS）可逆转并导致复发。在这里，我们的目标是描绘 TIS 逆转机制，以进行潜在的治疗干预，以防止 GBM 复发。从 GBM 患者来源的原代培养物和模拟临床情况的细胞系中捕获残留衰老 (RS) 和残留衰老结束 (ERS) 细胞。通过 RNA 测序、转录物/蛋白质验证、敲除/抑制剂研究、ChIP RT-PCR、生化测定和 IHC 来了解 TIS 逆转的机制。在 GBM 原位小鼠模型中进行体内验证。转录组分析显示 ER 应激-UPR 和衰老相关分泌表型 (SASP) 与 TIS 诱导和逆转共表达。 RS 细胞大量产生和分泌 SASP 可以以与辐射无关的旁分泌方式诱导衰老、ROS、DNA 损伤和 ER 应激。中和 RS 分泌组 IL1β 中最显着富集的细胞因子，抑制 SASP 并延迟衰老逆转。从机制上讲，随着 SASP 和内质网中大量蛋白质的积累，RS 细胞表现出应激的 ER 形态、上调的 ER 应激标记以及通过 peIF2α-ATF4-CHOP 激活 PERK 通路，并在 ERS ​​中自发解决。 ChIP RT-PCR 显示 CHOP 占据 CXCL8/IL8、CDKN1A/p21 和 BCL2L1/BCLXL，有助于存活。 GSK2606414 的 PERK 敲除/抑制与辐射相结合，可在不使用 SASP 的情况下导致持续的 ER 应激和衰老。 RS 中的 PERKi 通过细胞凋亡起到衰老作用，并在体外和体内预防复发，改善总体生存。我们证明 PERK 介导的 UPR 调节衰老逆转，其抑制作用可作为胶质母细胞瘤的潜在衰老治疗选择。© 作者2024 年。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Glioblastoma due to recurrence is clinically challenging with 10-15months overall survival. Previously we showed therapy induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate TIS reversal mechanism for potential therapeutic intervention to prevent GBM recurrence.Residual senescent (RS) and End of Residual Senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenario. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays and IHCs were performed for mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model.Transcriptome analysis showed co-expression of ER stress-UPR and senescence associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, ROS, DNA damage and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in Endoplasmic reticulum, RS cells displayed stressed ER morphology, upregulated ER stress markers and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21 and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival.We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.