Diphenyl Disulfide Exerts Dual Cytotoxic Effects by Inducing Ferroptosis and Apoptosis in Melanoma Cells

Melanoma is a highly aggressive and heterogeneous form of skin cancer with limited effective treatment options. Although substantial progress has been made in immunotherapy, chemotherapy still serves as an essential alternative therapeutic strategy for many patients. Diphenyl disulfide (DPDS), a small molecule composed of two phenyl groups linked by a disulfide bond, has been reported to exert antioxidant and anticancer activities across several types of malignancies. In this study, we examined the cytotoxic effects of DPDS on melanoma cells and investigated the underlying mechanisms responsible for its antitumor activity. Our results showed that DPDS induces both ferroptosis and apoptosis in melanoma cells in a time-dependent manner. At 24 h, DPDS promoted lipid peroxidation, enhanced xCT ubiquitination, and reduced GPX4 expression, all of which are characteristic hallmarks of ferroptosis. Whereas at 48 h, apoptosis occurred, likely because of NRF2 phosphorylation inhibition, which initially protected against cell death. Additionally, DPDS inhibited the PI3K/AKT/mTOR pathway, leading to decreased mTOR expression and increased autophagy levels. Furthermore, the inhibition of ferroptosis or autophagy partially restored cell viability, suggesting a complex interplay between these pathways in DPDS-induced cytotoxicity. These findings highlight that DPDS may be a potential therapeutic agent for melanoma that functions by leveraging dual programmed cell death mechanisms and targeting the PI3K/AKT/mTOR signaling pathway.