UBE2C-mediated ubiquitination of ACSL4 inhibits ferroptosis and promotes gastric cancer progression.

Gastric cancer (GC) is a major malignancy with a poor prognosis and high recurrence rate. The role of UBE2C, an E3 ubiquitin ligase, in gastric cancer progression was investigated. Data from TCGA and GEO datasets revealed significant upregulation of UBE2C in gastric cancer tissues, with a negative correlation between UBE2C and ACSL4, a key regulator of ferroptosis. The expression of UBE2C was manipulated in gastric cancer cell lines, and silencing of UBE2C significantly reduced cell proliferation, migration, and invasion. Additionally, an increase in reactive oxygen species (ROS) and iron ion accumulation suggested that UBE2C inhibition could promote ferroptosis. Further experiments showed that UBE2C ubiquitinates ACSL4, leading to its degradation, which suppressed ferroptosis in gastric cancer cells. Rescue experiments confirmed that silencing ACSL4 reversed the effects of UBE2C on cell proliferation and migration. In vivo experiments with GSH treatment alleviated the tumor-promoting effects of UBE2C overexpression, further supporting the regulatory role of UBE2C in ferroptosis. These findings suggest that UBE2C-mediated inhibition of ferroptosis through the ubiquitination of ACSL4 contributes to gastric cancer progression, and targeting this pathway may offer a new therapeutic strategy for gastric cancer.