UBE2D2 promotes gastric cancer progression by inhibiting ferroptosis through autophagy-dependent stabilization of CST1.

Gastric cancer peritoneal metastasis (GCPM) is an aggressive condition with poor survival, underscoring the need for new therapeutic targets. This study investigates the role of ubiquitin-conjugating enzyme E2 D2 (UBE2D2) in gastric cancer (GC). Analysis of clinical samples revealed that UBE2D2 is overexpressed in GC tissues and correlates with poor prognosis. Functional in vitro and in vivo experiments demonstrated that UBE2D2 knockdown suppresses GC cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT). Through proteomic screening, Cystatin SN (CST1) was identified as a key downstream target of UBE2D2. Further mechanistic studies showed that UBE2D2 promotes autophagy-dependent degradation of CST1, which consequently destabilizes glutathione peroxidase-4 (GPx4)-a central regulator of ferroptosis. UBE2D2 knockdown enhanced reactive oxygen species (ROS) accumulation and induced ferroptosis via the CST1-GPx4 axis. These findings indicate that UBE2D2 acts as an oncogene in GC by inhibiting ferroptosis through CST1 stabilization. Targeting the UBE2D2-CST1-GPx4 pathway induces ROS-mediated ferroptosis and suppresses tumor progression, suggesting a promising therapeutic strategy for GCPM.