RNF128 promotes gastric cancer progression by inhibiting autophagy-dependent ferroptosis through Beclin1...

As an important protein post-translational modification process, ubiquitination plays an indispensable role in the regulation of gastric cancer (GC) occurrence and development. And recent studies have demonstrated that this modification is closely related to regulated cell death. This suggests that our therapeutic approach to inhibit the malignant progression of GC by regulating the intracellular death mode through ubiquitination modification becomes possible. Although ubiquitination modification has been well described in some tumorigenesis, its potential role and specific mechanisms are still unknown. In the present study, we identified RNF128, an E3 ubiquitin ligase with a RING structural domain, whose expression was significantly increased in GC. In-depth studies showed that knockdown of RNF128 significantly inhibited GC cell proliferation and increased intracellular autophagic flux and lipid peroxidation production, and we hypothesized that autophagy-dependent ferroptosis might be the main mode of death mediated by RNF128. Mechanistically, RNF128 directly binds and ubiquitinates degradation of Beclin1 through its PA structural domain and significantly inhibits the Beclin1/solute transport family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4) axis. Taken together, our study reports for the first time that RNF128 acts as a tumor promoter to inhibit autophagy-dependent ferroptosis in GCs by targeting Beclin1. These data provide new insights into the activation of intracellular ferroptosis to inhibit malignant tumor progression and are expected to provide a new strategy for molecular therapy in clinical GC patients.