失调的去泛素化酶 (DUB) 作为内在癌基因或肿瘤抑制基因发挥作用，并参与癌症的化疗耐药性。然而，其在神经母细胞瘤中的功能和确切的分子机制在很大程度上仍不清楚。这里，基于标准差值的R2筛选策略用于识别4期神经母细胞瘤中最重要的DUB，USP44。我们验证了USP44调节的作用通过顺铂治疗的体外和体内实验，揭示了神经母细胞瘤中USP44调节和顺铂敏感性相关的分子机制。我们发现USP44低表达与神经母细胞瘤患者的不良预后相关。 USP44 的过表达增强了神经母细胞瘤细胞在体外和体内对顺铂的敏感性。从机制上讲，USP44通过去除Lys30位点K48连接的多聚泛素链来招募并稳定E3泛素连接酶STUB1，而STUB1进一步增强Lys453位点K48连接的多聚泛素化，促进其蛋白质降解，从而增强线粒体活性氧的积累(mROS)，进而促进神经母细胞瘤细胞凋亡和顺铂敏感性。此外，LRPPRC 的过表达逆转了 USP44 对顺铂处理的神经母细胞瘤细胞凋亡的促进作用。我们的研究结果表明，USP44-STUB1-LRPPRC 轴在神经母细胞瘤化疗耐药中发挥着关键作用，并为神经母细胞瘤治疗和预后提供了潜在靶标。©作者 2024。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。

Dysregulated deubiquitinating enzymes (DUBs) execute as intrinsic oncogenes or tumor suppressors and are involved in chemoresistance in cancers. However, the functions and exact molecular mechanisms remain largely unclear in neuroblastoma.Here, a R2 screening strategy based on the standard deviation values was used to identify the most important DUB, USP44, in neuroblastoma with stage 4. We validated the role of USP44 regulation upon cisplatin treatment in vitro and in vivo experiments, revealing the molecular mechanisms associated with USP44 regulation and cisplatin sensitivity in neuroblastoma.We found that low USP44 expression was associated with an inferior prognosis in neuroblastoma patients. Overexpression of USP44 enhanced neuroblastoma cell sensitivity to cisplatin in vitro and in vivo. Mechanistically, USP44 recruited and stabilized the E3 ubiquitin ligase STUB1 by removing its K48-linked polyubiquitin chains at Lys30, and STUB1 further reinforced the K48-linked polyubiquitination of LRPPRC at Lys453 and promoted its protein degradation, thus enhancing the accumulation of mitochondrial reactive oxygen species (mROS), in turn facilitating neuroblastoma cell apoptosis and cisplatin sensitivity. Additionally, overexpression of LRPPRC reversed the promoting effect of USP44 on cell apoptosis in cisplatin-treated neuroblastoma cells.Our findings demonstrate that the USP44-STUB1-LRPPRC axis plays a pivotal role in neuroblastoma chemoresistance and provides potential targets for neuroblastoma therapy and prognostication.© 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.