泛素-蛋白酶和自噬-溶酶体系统合作调节细胞内蛋白质水平。蛋白质稳态失调是恶性肿瘤的中心特征。编码泛素-蛋白酶系统26S蛋白酶非ATP酶调节亚基2（PSMD2）的基因是各种癌症的癌基因。然而，PSMD2在自噬中的详细作用及其与食管鳞癌（ESCC）的肿瘤发生关系尚不清楚。本研究探讨了PSMD2在ESCC自噬背景下的肿瘤促进作用。分子学方法包括DAPgreen染色、5-Ethynyl-2'-deoxyuridine（EdU）、细胞计数试剂盒8（CCK8）、集落形成、Transwell细胞穿透试验、细胞转染、异种移植模型、免疫印迹和免疫组织化学分析用于研究PSMD2在ESCC细胞中的作用。使用数据独立采集（DIA）定量蛋白质组学分析和救治实验研究了PSMD2在ESCC细胞中的作用。我们证明，PSMD2的过表达通过抑制自噬促进ESCC细胞生长，并与ESCC患者的肿瘤进展和不良预后相关。DIA定量蛋白质组学分析显示，谷氨酰丙酸合成酶1（ASS1）和PSMD2水平在ESCC肿瘤中呈显著正相关。进一步研究表明，PSMD2通过上调ASS1激活mTOR通路抑制自噬。PSMD2在抑制ESCC自噬中发挥重要作用，并代表了预测预后和ESCC患者治疗靶点的有前途的生物标志物。©2023年作者。

The ubiquitin-proteasome and autophagy-lysosomal systems collaborate in regulating the levels of intracellular proteins. Dysregulation of protein homeostasis is a central feature of malignancy. The gene encoding 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) of the ubiquitin-proteasome system is an oncogene in various types of cancer. However, the detailed role of PSMD2 in autophagy and its relationship to tumorigenesis in esophageal squamous cell carcinoma (ESCC) remain unknown. In the present study, we have investigated the tumor-promoting roles of PSMD2 in the context of autophagy in ESCC.Molecular approaches including DAPgreen staining, 5-Ethynyl-2'-deoxyuridine (EdU), cell counting kit 8 (CCK8), colony formation, transwell assays, and cell transfection, xenograft model, immunoblotting and Immunohistochemical analysis were used to investigate the roles of PSMD2 in ESCC cells. Data-independent acquisition (DIA) quantification proteomics analysis and rescue experiments were used to study the roles of PSMD2 in ESCC cells.We demonstrate that the overexpression of PSMD2 promotes ESCC cell growth by inhibiting autophagy and is correlated with tumor progression and poor prognosis of ESCC patients. DIA quantification proteomics analysis shows a significant positive correlation between argininosuccinate synthase 1 (ASS1) and PSMD2 levels in ESCC tumors. Further studies indicate that PSMD2 activates the mTOR pathway by upregulating ASS1 to inhibit autophagy.PSMD2 plays an important role in repressing autophagy in ESCC, and represents a promising biomarker to predict prognosis and a therapeutic target of ESCC patients.© 2023. The Author(s).