2. Academic Validation
  3. Diphenyl Disulfide Exerts Dual Cytotoxic Effects by Inducing Ferroptosis and Apoptosis in Melanoma Cells

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

  • Arch Immunol Ther Exp (Warsz). 2025 Dec 20;74(1). doi: 10.2478/aite-2026-0007.
Sheng-Yuan Chen 1 2,  En-De Shu 3,  Jiann-Jyh Huang 4,  Yen-Chun Chen 3,  Sheng-Kai Hsu 3,  Wen-Tsan Chang 5 6 7,  I-Ling Lin 8,  Chia-Hung Kuo 9,  Ming-Fong Tsai 10,  Zhi-Hong Wen 1 11,  Chien-Chih Chiu 3 8 12 13 14
Affiliations

Affiliations

  • 1 Department of Marine Biotechnology and Research, National Sun Yat-sen University, Kaohsiung, 804, Taiwan.
  • 2 Zuoying Armed Forces General Hospital, Kaohsiung 813, Taiwan.
  • 3 Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 4 Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
  • 5 Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
  • 6 Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 7 Transplantation Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
  • 8 Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 9 Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.
  • 10 Department of Electronic Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 807, Taiwan.
  • 11 National Museum of Marine Biology and Aquarium, Pingtung, 944, Taiwan.
  • 12 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
  • 13 Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 14 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
PMID: 41420872 DOI: 10.2478/aite-2026-0007
Abstract

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.

Keywords

Apoptosis; Autophagy; Diphenyl disulfide; Ferroptosis; Melanoma; PI3K/AKT/mTOR pathway.

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