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作者

Shanlong Zhang, Li Kang, Xiaoxue Dai, Junlan Chen, Zhengtao Chen, Meixiang Wang, Huantong Jiang, Xin Wang, Suqin Bu, Xinyuan Liu, Guohui Zhang, Hua Tang

作者单位

Affiliations ¹ Department of Clinical Laboratory, The Second Affiliated Hospital of Shandong First Medical University, 271000, Taian, Shandong, China. ² Department of Immunology, School of Clinical and Basic Medical, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, Shandong, China. ³ Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 250014, Jinan, Shandong, China Institute of Infection and Immunity, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250000, Jinan, Shandong, China. Electronic address: tanghuazhang218@16 com. Institute of Infection and Immunity, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250000, Jinan, Shandong, China. ⁴ The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine of Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, 430079, Wuhan, China. ⁵ Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 250014, Jinan, Shandong, China. ⁶ Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 250014, Jinan, Shandong, China

刊名

Free radical biology & medicine

年份

2022

ISSN

1873-4596

关键词

DHODH Ferroptosis Lipid peroxidation Type-I IFN cGAS–STING

摘要

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 within the tumor. However, the exact underlying ...更多

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 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 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase -mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon , 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-induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl. 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.收起

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