RAB17 downregulation elicits antitumor impacts in prostate cancer by triggering ferroptotic cell death through the regulation of TfR1-mediated iron overload.

Increasing evidence suggests that Ras-related protein RAB17 plays a crucial role in tumor progression. Our preliminary data demonstrated that RAB17 is overexpressed in prostate cancer; however, its specific function in this malignancy is still poorly understood. This study sought to systematically clarify the functional role of RAB17 in prostate cancer, delineate its underlying molecular mechanisms, and evaluates its therapeutic potential. Analysis of clinical samples revealed that elevated RAB17 levels correlate with poorer overall survival in prostate cancer patients. Gene knockdown experiments demonstrated that silencing RAB17 exhibited notable tumor-suppressive effects in prostate cancer cells. Further investigations revealed that RAB17 knockdown increased intracellular iron concentrations and elevated lipid peroxidation levels, thereby triggering ferroptosis. Inhibiting ferroptosis significantly rescued the cancer-inhibiting impact elicited by RAB17 depletion. Notably, RAB17 was identified to interact with the iron uptake receptor transferrin receptor 1 (TfR1), promoting its degradation. Consequently, RAB17 knockdown increased TfR1 protein levels, enhancing iron influx and leading to iron overload and ferroptosis. Silencing TfR1 in RAB17 knockdown cells significantly reversed the tumor-suppressive and ferroptosis-inducing effects. In vivo experiments demonstrated that targeting RAB17 significantly delayed xenograft tumor growth associated with the induction of ferroptotic changes in tumor tissues. In conclusion, RAB17 is overexpressed in prostate cancer and exerts a tumor-promoting function. Silencing RAB17 induces ferroptosis through TfR1-mediated iron overload, thereby exerting tumor-suppressive effects. The RAB17-TfR1-ferroptosis axis may represent a pivotal modulator of prostate cancer and a promising candidate for targeted therapeutic intervention.