泛素化是一种普遍且高度动态的可逆翻译后修饰，受到去泛素化酶 (DUB) 超家族的严格调控。其中，含有OTU结构域的泛素醛结合蛋白1（OTUB1）作为OTU去泛素化家族的重要成员脱颖而出，在多种癌症中作为肿瘤调节剂发挥着关键作用。然而，其在 BLCA 中的具体参与（BLCA）及其临床意义仍然不明确。本研究旨在阐明 BLCA 中 OTUB1 的生物功能及其对临床预后的影响。我们的调查显示 BLCA 中 OTUB1 表达升高，与不利的临床结果相关。通过体内和体外实验，我们证明 OTUB1 水平升高会促进 BLCA 肿瘤的发生和进展，并赋予顺铂治疗耐药性。值得注意的是，我们建立了一个涉及 OTUB1、β-连环蛋白、坏死性凋亡和 BLCA 的综合网络，描绘了它们的调控相互作用。从机制上讲，我们发现 OTUB1 通过去泛素化和稳定 β-catenin 发挥其影响，导致其核转位。随后，核β-catenin增强c-myc和cyclin D1的转录活性，同时抑制RIPK3和MLKL的表达，从而促进BLCA进展和顺铂耐药。重要的是，我们的临床数据表明 OTUB1/β-连环蛋白/RIPK3/MLKL 轴有望成为 BLCA 的潜在生物标志物。© 作者。

Ubiquitination, a prevalent and highly dynamic reversible post-translational modification, is tightly regulated by the deubiquitinating enzymes (DUBs) superfamily. Among them, OTU Domain-Containing Ubiquitin Aldehyde-Binding Protein 1 (OTUB1) stands out as a critical member of the OTU deubiquitinating family, playing a pivotal role as a tumor regulator across various cancers. However, its specific involvement in BLCA (BLCA) and its clinical significance have remained ambiguous. This study aimed to elucidate the biofunctions of OTUB1 in BLCA and its implications for clinical prognosis. Our investigation revealed heightened OTUB1 expression in BLCA, correlating with unfavorable clinical outcomes. Through in vivo and in vitro experiments, we demonstrated that increased OTUB1 levels promote BLCA tumorigenesis and progression, along with conferring resistance to cisplatin treatment. Notably, we established a comprehensive network involving OTUB1, β-catenin, necroptosis, and BLCA, delineating their regulatory interplay. Mechanistically, we uncovered that OTUB1 exerts its influence by deubiquitinating and stabilizing β-catenin, leading to its nuclear translocation. Subsequently, nuclear β-catenin enhances the transcriptional activity of c-myc and cyclin D1 while suppressing the expression of RIPK3 and MLKL, thereby fostering BLCA progression and cisplatin resistance. Importantly, our clinical data suggest that the OTUB1/β-catenin/RIPK3/MLKL axis holds promise as a potential biomarker for BLCA.© The author(s).