Zhao Caiqing, Qi Jialing, Zhang Zhenze, Feng Qi, Fang Ziling, Fang Nian
Department of Gastroenterology, The 3rd Affiliated Hospital (The First Hospital of Nanchang), Nanchang University, Nanchang, China.
The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Front Oncol. 2025 Aug 27;15:1628729. doi: 10.3389/fonc.2025.1628729. eCollection 2025.
Gastric cancer (GC) is a globally prevalent malignant tumor, causing approximately 770,000 deaths in 2020, ranking fourth among all cancers. The tripartite motif (TRIM) protein family is involved in various cellular regulations and has become a key player in the pathogenesis of gastric cancer. This review explores the therapeutic potential of TRIM proteins in gastric cancer, from signaling pathway regulation to precision targeting strategies. Structurally, there are differences in the C-terminal domain of TRIM proteins, which determine their subgroup classification and substrate recognition. Functionally, they regulate multiple signaling pathways that are crucial for the development of gastric cancer. Clinically, many TRIM proteins serve as promising diagnostic and prognostic biomarkers. In terms of therapy, targeting TRIM proteins holds great potential. Strategies include developing small molecule inhibitors targeting specific TRIM domains, such as inhibitors targeting the bromodomain of TRIM24, and exploring PROTAC technology to degrade oncogenic TRIM proteins. Combination immunotherapy targeting TRIM-related pathways may also provide new therapeutic options. However, challenges persist, Including limited understanding of heterotypic polyubiquitination targets/functions of TRIM proteins, insufficient mechanistic/epidemiological insights into their immunomodulatory roles in the tumor microenvironment, underdeveloped TRIM inhibitors for gastric cancer, unevaluated pharmacokinetics/toxicity of inhibitors in preclinical models, and the need to construct complete TRIM biological systems. In summary, TRIM proteins are deeply involved in the biological processes of gastric cancer, and understanding their functions and regulation could lead to the development of more effective precision targeting strategies for gastric cancer treatment.
胃癌（GC）是一种全球流行的恶性肿瘤，2020年导致约77万人死亡，在所有癌症中排名第四。三联基序（TRIM）蛋白家族参与多种细胞调节，已成为胃癌发病机制中的关键因素。本综述探讨了TRIM蛋白在胃癌中的治疗潜力，从信号通路调节到精准靶向策略。在结构上，TRIM蛋白的C末端结构域存在差异，这决定了它们的亚组分类和底物识别。在功能上，它们调节对胃癌发展至关重要的多种信号通路。在临床上，许多TRIM蛋白是有前景的诊断和预后生物标志物。在治疗方面，靶向TRIM蛋白具有很大潜力。策略包括开发针对特定TRIM结构域的小分子抑制剂，如针对TRIM24溴结构域的抑制剂，以及探索PROTAC技术以降解致癌性TRIM蛋白。靶向TRIM相关通路的联合免疫疗法也可能提供新的治疗选择。然而，挑战依然存在，包括对TRIM蛋白的异型多聚泛素化靶点/功能了解有限，对其在肿瘤微环境中的免疫调节作用的机制/流行病学认识不足，用于胃癌的TRIM抑制剂开发不完善，抑制剂在临床前模型中的药代动力学/毒性未评估，以及需要构建完整的TRIM生物学系统。总之，TRIM蛋白深度参与胃癌的生物学过程，了解它们的功能和调节可能会导致开发出更有效的胃癌精准靶向治疗策略。
