Curcumin Analogues Trigger HMOX1-Mediated Ferroptosis to Halt Endometrial Cancer Growth

Background: Advanced endometrial Cancer remains challenging to treat due to limited therapeutic options and drug resistance. Ferroptosis, an iron-dependent form of cell death, offers a potential strategy for overcoming resistance. Curcumin analogues with improved bioavailability, such as HO-3867 and AKT-100, exhibit potent anti-cancer activity, but their mechanisms remain under-explored.

Methods: KLE, Hec50co and Ishikawa endometrial Cancer cells were treated with HO-3867 or AKT-100. RNA Sequencing, qPCR, and immunoblotting assessed ferroptosis-related gene expression, focusing on HMOX1. Intracellular iron and ROS were measured via FerroOrange and DCFH-DA staining. Cytotoxicity and colony formation were evaluated using CyQUANT assays, with pharmacological inhibitors (ZnPP, Liproxstatin-1, Z-VAD-FMK) and HMOX1 siRNA to dissect the roles of Ferroptosis and Apoptosis.

Results: Both analogues upregulated multiple Ferroptosis genes, prominently HMOX1. AKT-100 increased intracellular iron and ROS levels. Inhibition of HMOX1, Ferroptosis, or Apoptosis partially rescued cell viability, while HMOX1 knockdown enhanced clonogenic growth, confirming its key role in AKT-100-mediated cytotoxicity.

Conclusions: HO-3867 and AKT-100 induce HMOX1-mediated Ferroptosis and Apoptosis, effectively suppressing endometrial Cancer cell growth. These findings support the therapeutic potential of curcumin analogues and provide a foundation for in vivo studies targeting HMOX1 in endometrial Cancer.