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Background <p>Ferroptosis has been correlated with the cancer chemotherapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. The GPX4-mediated signaling pathway is one of the most central pathways regulating ferroptosis. However, most currently available GPX4 inhibitors are covalent inhibitors, with limited structural diversity.</p> Results <p>Here, we explored the potential and related molecular mechanisms of Compound AI-3p, a novel GPX4 inhibitor designed by linking an isoxazole pharmacophore to an anthraquinone core, for the treatment of cisplatin (DDP)-resistant ovarian cancer. Compound AI-3p showed significant cytotoxicity against DDP-resistant ovarian cancer cells (SKOV3/DDP), with a higher selectivity index against SKOV3/DDP and lower cytotoxicity against normal ovarian epithelial cells (IOSE80) than DDP. Molecular docking revealed that AI-3p forms a hydrogen bond with Leu130 in the catalytically active tetramer of GPX4, as well as carbon-hydrogen bonds with Sec 46, Gln81, and Lys135. Further validation via molecular dynamics simulations and Cellular Thermal Shift Assay (CETSA) confirmed that AI-3p can form a stable complex with GPX4. Mechanistic study revealed that Compound AI-3p could trigger the ferroptosis via inhibition of the GPX4/GSH axis, inducing reactive oxygen species (ROS) production, Lipid peroxidation, iron ion accumulation, Labile Iron Pool accumulation (LIP) accumulation, and a reduction in GSH content.</p> Conclusions <p>This study identifies Compound AI-3p as a novel GPX4 inhibitor that triggers ferroptosis, offering a potential breakthrough in the development of future drugs to combat cisplatin-resistant ovarian cancer development.</p> Graphical abstract <p></p>

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Mechanistic insights into a novel GPX4 inhibitor Compound AI-3p reversing cisplatin-resistance in ovarian cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Bingyu Wang,
  • Dan Li,
  • Linfang Lai,
  • Ying Lu,
  • Ting-an Wang,
  • Jiaxing Song,
  • Pingzhen Wei,
  • Huaxin Hou,
  • Mingyuan Zhang,
  • Chunmiao Wang

摘要

Background

Ferroptosis has been correlated with the cancer chemotherapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. The GPX4-mediated signaling pathway is one of the most central pathways regulating ferroptosis. However, most currently available GPX4 inhibitors are covalent inhibitors, with limited structural diversity.

Results

Here, we explored the potential and related molecular mechanisms of Compound AI-3p, a novel GPX4 inhibitor designed by linking an isoxazole pharmacophore to an anthraquinone core, for the treatment of cisplatin (DDP)-resistant ovarian cancer. Compound AI-3p showed significant cytotoxicity against DDP-resistant ovarian cancer cells (SKOV3/DDP), with a higher selectivity index against SKOV3/DDP and lower cytotoxicity against normal ovarian epithelial cells (IOSE80) than DDP. Molecular docking revealed that AI-3p forms a hydrogen bond with Leu130 in the catalytically active tetramer of GPX4, as well as carbon-hydrogen bonds with Sec 46, Gln81, and Lys135. Further validation via molecular dynamics simulations and Cellular Thermal Shift Assay (CETSA) confirmed that AI-3p can form a stable complex with GPX4. Mechanistic study revealed that Compound AI-3p could trigger the ferroptosis via inhibition of the GPX4/GSH axis, inducing reactive oxygen species (ROS) production, Lipid peroxidation, iron ion accumulation, Labile Iron Pool accumulation (LIP) accumulation, and a reduction in GSH content.

Conclusions

This study identifies Compound AI-3p as a novel GPX4 inhibitor that triggers ferroptosis, offering a potential breakthrough in the development of future drugs to combat cisplatin-resistant ovarian cancer development.

Graphical abstract