Abstract
Deubiquitinating enzymes (DUBs) are crucial for regulating the degradation of specific proteins and represent a novel therapeutic direction in cancer. In gastric cancer, USP4 levels are significantly elevated, though its therapeutic potential remains underexplored. Our study demonstrates that USP4 plays a pivotal role in gastric cancer cells via the autophagy-dependent ferroptosis pathway. Specifically, USP4 selectively removes Lys48-linked polyubiquitin chains through its deubiquitination activity at the C311 site, stabilizing the A2AR protein. This action precisely modulates autophagy and inhibits ferroptosis, thereby promoting gastric cancer progression. Additionally, our findings indicate that targeting USP4 or A2AR can activate autophagy and restore the ferroptosis process, which is essential for autophagy-dependent ferroptosis. Consequently, the USP4-A2AR signaling pathway is critically important for the survival of gastric cancer cells and represents a potential therapeutic target for gastric cancer.