Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase

Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl 2 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl 2 downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl 2 enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS–STING signaling pathway. When inhibiting the cGAS–STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl 2 -induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl 2 . Mechanistically, these results revealed that Manganese treatment-activated cGAS–STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.