Luteolin-ManganeseNanozyme Induces Apoptosis andFerroptosis for Enhanced Cancer Therapy

Cancer presents a significant global public health challenge that impacts millions of individuals worldwide. The incorporation of natural products into cancer treatment has the potential to mitigate many of the side effects commonly associated with chemotherapy. This study builds on the advantages of enhancing the anticancer activity of natural flavonoids through metal chelation by synthesizing a natural antioxidant flavonoid complex, termed Lu–Mn nanozyme, which involves the chelation of luteolin with manganese ions. In vitro experiments demonstrated that Lu–Mn exhibits a strong affinity for hydrogen peroxide (H₂O₂) and effectively catalyzes the generation of hydroxyl radicals (•OH) from H₂O₂ within the tumor microenvironment. The administration of the Lu–Mn nanozyme not only induced apoptosis in tumor cells by upregulating the expression of cleaved caspase3 and caspase9 but also activated ferroptosis through downregulation of the NRF2-GPX4 signaling pathway. Furthermore, animal studies have shown that Lu–Mn possesses significant antitumor efficacy and a favorable safety profile. Collectively, these findings suggest that luteolin, through its chelation with metal ions, has considerable potential for application in cancer treatment.