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Ferroptosis is a type of programmed cell death characterized by accumulation of free iron, reactive oxygen species generation and lipid peroxidation and is distinct from other types of regulated cell deaths such as apoptosis, necrosis and autophagy. Ferroptosis is distinct from other programmed cell deaths for its iron dependence and its significant role in tumor suppression. Therefore, harnessing ferroptosis may offer promising avenues for cancer therapy. In the present review, the different pathways that lead to ferroptosis, the genes and transcription factors involved in both iron and lipid metabolism, as well as the impact of small‑molecule alterations on the regulation of ferroptotic cell death, were discussed. Furthermore, the emergence of combination therapies with ferroptosis‑inducing molecules that overcome resistance to conventional chemotherapy, particularly in solid tumors, were highlighted. Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less