依赖于各种机制，包括TMZ外流、自噬、碱基切除修复途径和O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的水平，TMZ治疗效果在胶质母细胞瘤中得到确定。在这里，我们报告了一种潜在的、能够降低TMZ外流并通过自溶酶体在早期促进PARP1降解的新型小分子抑制剂（SMI）EPIC-1042（C20H28N6）。EPIC-1042通过受体基于虚拟筛选获取。共免疫沉淀和pull-down实验被用来验证EPIC-1042的阻断效果。西方博莱特、共免疫沉淀和免疫荧光检测被用于阐明EPIC-1042的潜在机制。利用体内实验验证了EPIC-1042增强TMZ对胶质母细胞瘤细胞敏感性的疗效。EPIC-1042通过物理上干扰PTRF/Cavin1和caveolin-1的相互作用来降低小细胞外囊泡（sEVs）的分泌，从而减少TMZ外流。同时，通过增加p62的表达，EPIC-1042诱导PARP1自噬降解，使更多的p62与PARP1结合，并特异促进PARP1进入自溶酶体发生降解。此外，EPIC-1042最后还抑制了自噬通路。EPIC-1042的应用增强了胶质母细胞瘤体内TMZ的疗效。EPIC-1042通过防止TMZ外流、通过自溶酶体诱导PARP1降解从而干扰碱基切除修复途径和MGMT的招募，以及抑制后期的自噬通路加强了TMZ的效果。因此，本研究为胶质母细胞瘤治疗提供了一种结合TMZ与EPIC-1042的新型治疗策略。© 本文作者 2023。牛津大学出版社代表神经肿瘤学会发表。保留所有权利。如需授权，请发送电子邮件至：journals.permissions@oup.com。

Temozolomide (TMZ) treatment efficacy in glioblastoma is determined by various mechanisms such as TMZ efflux, autophagy, base excision repair (BER) pathway, and the level of O 6-methylguanine-DNA methyltransferase (MGMT). Here, we reported a novel small-molecular inhibitor (SMI) EPIC-1042 (C20H28N6) with the potential to decrease TMZ efflux and promote PARP1 degradation via autolysosomes in the early stage.EPIC-1042 was obtained from Receptor-based virtual screening. Co-immunoprecipitation and pull-down assays were applied to verify the blocking effect of EPIC-1042. Western blotting, Co-immunoprecipitation and immunofluorescence were used to elucidate the underlying mechanisms of EPIC-1042. In vivo experiments were performed to verify the efficacy of EPIC-1042 in sensitizing glioblastoma cells to TMZ.EPIC-1042 physically interrupted the interaction of PTRF/Cavin1 and caveolin-1, leading to reduced secretion of small extracellular vesicles (sEVs) to decrease TMZ efflux. It also induced PARP1 autophagic degradation via increased p62 expression that more p62 bound to PARP1 and specially promoted PARP1 translocation into autolysosomes for degradation in the early stage. Moreover, EPIC-1042 inhibited autophagy flux at last. The application of EPIC-1042 enhanced TMZ efficacy in glioblastoma in vivo.EPIC-1042 reinforced the effect of TMZ by preventing TMZ efflux, inducing PARP1 degradation via autolysosomes to perturb the BER pathway and recruitment of MGMT, and inhibiting autophagy flux in the later stage. Therefore, this study provided a novel therapeutic strategy using the combination of TMZ with EPIC-1042 for glioblastoma treatment.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.