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

Abstract

BackgroundAdvanced 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. MethodsKLE, 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. ResultsBoth 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. ConclusionsHO-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. O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/689080v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@610bcorg.highwire.dtl.DTLVardef@34d8eaorg.highwire.dtl.DTLVardef@18d2a5aorg.highwire.dtl.DTLVardef@d7b4f3_HPS_FORMAT_FIGEXP M_FIG C_FIG