Enhancing radiotherapy in triple-negative breast cancer with hesperetin-induced ferroptosis via AURKA targeting nanocomposites

Triple-negative breast cancer (TNBC) is an aggressive cancer type that lacks targeted treatment options. Ferroptosis, a novel therapeutic strategy, induces cell death by disrupting the oxidative-reductive balance. Hesperetin, a potential TNBC therapeutic drug, has unidentified regulatory targets. The objective of this study was to explore the potential targets of hesperetin in TNBC and investigate whether the nanocomposites carrier hesperetin-loaded ferroptosis-inducing nanocomposites (HFPN), which activates ferroptosis, can enhance the anti-tumor efficacy of hesperetin. Bioinformatics methods were employed to screen hesperetin targets in TNBC, and a molecular docking model between hesperetin and the core target aurora kinase A (AURKA) was successfully constructed. The stability and anti-tumor activity of HFPN were validated in cell and mouse models, including tumor suppression and increased radiation sensitivity. These results suggest that HFPN can regulate the core target AURKA in TNBC, disrupt tumor oxidative-reductive balance, promote ferroptosis in tumor cells, and ultimately enhance the effectiveness of radiation therapy for TNBC.