泛素化在肿瘤进展中发挥着关键的调节作用。在泛素-蛋白酶体系统（UPS）的组成部分中，泛素-蛋白质连接酶E3已成为关键分子。然而，E3 泛素连接酶的生物学功能及其在胃癌 (GC) 中协调糖酵解的潜在机制仍有待阐明。在本研究中，我们进行了全面的转录组分析，以确定 GC 中的核心 E3 泛素连接酶，然后在体外和体内广泛验证包含三部分基序的 50 (TRIM50) 的表达模式和临床意义。值得注意的是，我们发现 TRIM50 在 GC 组织中表达下调，与恶性进展和患者生存率低相关。从功能上讲，TRIM50的过表达抑制GC细胞增殖，并通过抑制肿瘤相关巨噬细胞（TAM）的M2极化间接减轻GC细胞的侵袭和迁移。从机制上讲，TRIM50 通过泛素化磷酸甘油酸激酶 1 (PGK1) 抑制糖酵解途径，从而直接抑制 GC 细胞增殖。同时，乳酸的减少导致TAMs的M2极化减弱，间接抑制GC细胞的侵袭和迁移。值得注意的是，GC 中 TRIM50 的下调是由 METTL3/YTHDF2 轴以 m6A 依赖性方式介导的。在我们的研究中，我们明确确定 TRIM50 是一种肿瘤抑制基因（TSG），通过泛素化 PGK1 有效抑制糖酵解和 GC 的恶性进展，从而为 GC 的诊断和治疗提供新的见解和有希望的靶标。© 作者）。

Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo. Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC.© The author(s).