Mechanistic insights and therapeutic potential of E3 ubiquitin ligases in gastric cancer development.

The ubiquitin-proteasome system (UPS) is the primary pathway for protein degradation in eukaryotic cells. E3 ubiquitin ligases regulate protein homeostasis through substrate-specific ubiquitination and play a crucial role in the onset, progression, and therapeutic resistance of gastric cancer (GC). This article systematically reviews the classification, functions, and regulatory mechanisms of E3 ubiquitin ligases in gastric cancer, including their roles in cell proliferation, invasion and metastasis, apoptosis, autophagy, ferroptosis, as well as their relationship with the gastric cancer microenvironment. Furthermore, this article discusses the molecular mechanisms by which E3 ligases contribute to the progression of gastric cancer through the Akt, Wnt/β-catenin, and NF-κB signaling pathways. It also summarizes potential therapeutic strategies targeting E3 ligases, such as small molecule inhibitors, PROTAC technology, molecular glues, and immunotherapy. Finally, the article explores mechanism of treatment resistance and potential solutions of E3 ligases in gastric cancer, providing a theoretical foundation for the development of new targeted therapies for this disease.