Curcumin analogues and HMOX1-mediated ferroptosis in endometrial cancer.

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Background: Advanced endometrial cancer remains challenging to treat due to limited therapeutic options and drug resistance. Ferroptosis, an iron-dependent form of regulated cell death, offers a potential strategy to overcome resistance. Methods: Human endometrial cancer cell lines (KLE, Hec50co, Ishikawa) were treated with bioavailable curcumin analogues HO-3867 or AKT-100. Ferroptosis-related gene expression was assessed by RNA sequencing, qPCR, and immunoblotting, focusing on heme oxygenase-1 (HMOX1). Intracellular iron and reactive oxygen species (ROS) were quantified using FerroOrange and DCFH-DA staining. Cell viability and clonogenic survival were evaluated via CyQUANT and colony-formation assays. Pharmacological inhibitors (ZnPP, Liproxstatin-1, Z-VAD-FMK) and HMOX1 siRNA were used to dissect ferroptosis and apoptosis contributions. Statistical analyses included one-way ANOVA with Tukey’s post hoc test for multiple comparisons; significance was set at p < 0.05. Results: Both analogues upregulated ferroptosis-associated genes, most prominently HMOX1. AKT-100 markedly increased intracellular iron and ROS. Inhibition of HMOX1, ferroptosis, or apoptosis partially rescued viability, while HMOX1 knockdown enhanced clonogenic survival, confirming its central role in AKT-100–mediated cytotoxicity. Conclusions: HO-3867 and AKT-100 activate HMOX1-driven ferroptosis and apoptosis to suppress endometrial cancer cell growth. These findings support further in vivo evaluation of HMOX1-targeted strategies as a therapeutic approach for advanced endometrial cancer.