Hinokitiol-iron complex is a ferroptosis inducer to inhibit triple-negative breast tumor growth

Ferroptosis is a unique cell death, dependent on iron and phospholipid peroxidation, involved in massive processes of physiopathology. Tremendous attention has been caught in oncology, particularly for those therapy-resistant cancers in the mesenchymal state prone to metastasis due to their exquisite vulnerability to ferroptosis. Therefore, a therapeutical ferroptosis inducer is now underway to be exploited. A natural compound, hinokitiol (hino), has been considered to be an iron chelator. We have a novel finding that hino complexed with iron to form Fe(hino) can function as a ferroptosis inducer in vitro. The efficiency, compared with the same concentration of iron, increases nearly 1000 folds. Other iron chelators, ferroptosis inhibitors, or antioxidants can inhibit Fe(hino) -induced ferroptosis. The complex Fe(hino) efficacy is further confirmed in orthotopic triple-negative breast cancer (TNBC) tumor models that Fe(hino) significantly boosted lipid peroxidation to induce ferroptosis and significantly reduced the sizes of TNBC cell-derived tumors. The drug's safety was also evaluated, and no detrimental side effects were found with the tested dosage. When entering cells, the chelated iron by hinokitiol as a complex Fe(hino) is proposed to be redox-active to vigorously promote the production of free radicals via the Fenton reaction. Thus, Fe(hino) is a ferroptosis inducer and, therapeutically, exhibits anti-TNBC activity.