Ferroptosis induction by curcumin through regulating the expression of glutathione peroxidase 4 in papillary thyroid...

To clarify the role of glutathione peroxidase 4 (GPX4)-mediated ferroptosis in curcumin-treated papillary thyroid carcinoma (PTC) cells and explore the underlying mechanisms. GPX4 expression and clinical relevance were analysed in 54 PTC tissues by immunohistochemistry. B-CPAP cells were used to assess proliferation, migration, apoptosis and cell cycle after curcumin treatment. Ferroptosis was evaluated by detecting malondialdehyde (MDA), reactive oxygen species (ROS), Fe²⁺ and glutathione (GSH) levels, with ferrostatin 1 (Fer-1) and agonists (RSL3) used for validation. Molecular docking and Western blot were performed to analyse GPX4 interaction and expression. A nude mouse xenograft model was established to evaluate in vivo effects. Elevated GPX4 expression correlated with poor prognosis in PTC, including increased lymph node and distant metastasis and reduced progression-free survival. In vitro studies showed that curcumin downregulated GPX4 and induced ferroptotic features, including increased MDA and ROS, elevated Fe²⁺ and decreased GSH. These changes were accompanied by inhibited proliferation and migration, as well as G2/M arrest. Importantly, the ferroptosis inhibitor Fer-1 reversed curcumin-induced cell death and partially restored migration, confirming ferroptosis as the primary anticancer mechanism. Molecular docking analysis suggested a possible interaction between curcumin and the GPX4 protein at the Gln-55 and Pro-155 residues; however, this prediction was not experimentally validated in the present study. Importantly, GPX4 overexpression partially rescued curcumin-induced loss of cell viability and lipid peroxidation, supporting a functional role for GPX4 in curcumin-induced ferroptosis. In vivo experiments showed that curcumin significantly suppressed tumour growth in the xenograft model without observable organ toxicity and reduced GPX4 expression in tumour tissues. This study shows that curcumin inhibits PTC progression via GPX4-mediated ferroptosis; GPX4 overexpression partially reversed these effects, supporting its functional role. These findings identify curcumin as a promising therapeutic agent for PTC treatment and suggest GPX4 as a potential therapeutic target.