有证据表明，BRCA1，特别是细胞质 BRCA1，通过各种机制在启动细胞凋亡中发挥重要作用。维持癌细胞中BRCA1的稳定性可能是一种有前途的乳腺癌治疗策略，特别是在缺乏适当治疗靶点的三阴性乳腺癌（TNBC）的情况下。此前有报道称组织蛋白酶 S (CTSS) 与 BRCA1 的 BRCT 结构域相互作用，导致泛素介导的降解。我们进一步研究了 BRCA1 Ser1387 磷酸化的关键作用，这是由电离辐射 (IR) 诱导的 ATM 激活介导的。该磷酸化事件被确定为 CTSS 介导的 BRCA1 泛素降解的关键因素。使用小分子或敲除系统对 CTSS 进行功能性抑制，通过恢复细胞质 BRCA1 的稳定性，在暴露于 IR 时使 TNBC 细胞变得敏感。细胞质 BRCA1 的增加导致抗凋亡 BCL2 的降解，这导致了 CTSS 抑制观察到的放射增敏作用。这些结果表明，抑制 CTSS 可能是通过抑制 CTSS 诱导的 BRCA1 降解介导的 BCL2 降解来实现 TNBC 细胞放射增敏的有效策略。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

There is evidence that BRCA1, particularly cytoplasmic BRCA1, plays a significant role in initiating apoptosis through various mechanisms. Maintaining the stability of BRCA1 in cancer cells may be a promising therapeutic strategy for breast cancer, especially in cases of triple-negative breast cancer (TNBC) lacking appropriate therapeutic targets. Previously, it was reported that cathepsin S (CTSS) interacts with the BRCT domain of BRCA1, leading to ubiquitin-mediated degradation. We further investigated the critical role of BRCA1 phosphorylation at Ser1387, which is mediated by ionizing radiation (IR)-induced activation of ATM. This phosphorylation event was identified as a key factor in CTSS-mediated ubiquitin degradation of BRCA1. The functional inhibition of CTSS, using small molecules or a knockdown system, sensitized TNBC cells when exposed to IR by restoring the stability of cytoplasmic BRCA1. The increase in cytoplasmic BRCA1 led to the degradation of anti-apoptotic BCL2, which was responsible for the radiosensitization effect observed with CTSS inhibition. These results suggest that inhibiting CTSS may be an effective strategy for radiosensitization in TNBC cells through BCL2 degradation that is mediated by inhibition of CTSS-induced BRCA1 degradation.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.