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

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

doi:10.1016/j.freeradbiomed.2022.10.004

Cited by 36 publications

(17 citation statements)

References 59 publications

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“…In addition, MnCl 2 enhanced the phosphorylation levels of STING, TBK1, and IRF3, and up‐regulated the expression of IFN produced by the cGAS‐STING pathway. [ 136 ]…”

Section: Combination Therapy Based On Nanotechnologymentioning

confidence: 99%

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

et al. 2023

Adv Healthcare Materials

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As the first line of host defense against pathogenic infections, innate immunity plays a key role in antitumor immunotherapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) pathway has attracted much attention because of the secretion of various proinflammatory cytokines and chemokines. Many STING agonists have been identified and applied into preclinical or clinical trials for cancer immunotherapy. However, the fast excretion, low bioavailability, nonspecificity, and adverse effects of the small molecule STING agonists limit their therapeutic efficacy and in vivo application. Nanodelivery systems with appropriate size, charge, and surface modification are capable of addressing these dilemmas. In this review, the mechanism of the cGAS-STING pathway is discussed and the STING agonists, focusing on nanoparticle-mediated STING therapy and combined therapy for cancers, are summarized. Finally, the future direction and challenges of nano-STING therapy are expounded, emphasizing the pivotal scientific problems and technical bottlenecks and hoping to provide general guidance for its clinical application.

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“…In addition, MnCl 2 enhanced the phosphorylation levels of STING, TBK1, and IRF3, and up‐regulated the expression of IFN produced by the cGAS‐STING pathway. [ 136 ]…”

Section: Combination Therapy Based On Nanotechnologymentioning

confidence: 99%

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

et al. 2023

Adv Healthcare Materials

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“…Specifically, Mn 2+ can potently stimulate cGAS–STING signaling and induce the release of type I interferon, while inhibiting the expression of DHODH in tumor cells. Considering the key role of DHODH as an antiferroptosis protein by maintaining mitochondrial homeostasis, Mn 2+ -induced dysregulation of DHODH will significantly increase the level of mitochondrial ROS and drive ferroptosis . It is thus anticipated that the dual pro-ferroptosis and immunostimulatory effects of Mn 2+ ions provide promising opportunities for ferroptosis-immunotherapy. − These noniron-containing Fenton-nanocatalytic systems offer effective opportunities for developing combinational antitumor modalities.…”

Section: Exploitation Of Tumor Metabolism For Ferroptosis Therapymentioning

confidence: 99%

Ferroptosis Nanomedicine: Clinical Challenges and Opportunities for Modulating Tumor Metabolic and Immunological Landscape

et al. 2023

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Ferroptosis, a type of regulated cell death driven by iron-dependent phospholipid peroxidation, has captured much attention in the field of nanomedicine since it was coined in 2012. Compared with other regulated cell death modes such as apoptosis and pyroptosis, ferroptosis has many distinct features in the molecular mechanisms and cellular morphology, representing a promising strategy for treating cancers that are resistant to conventional therapeutic modalities. Moreover, recent insights collectively reveal that ferroptosis is tightly connected to the maintenance of the tumor immune microenvironment (TIME), suggesting the potential application of ferroptosis therapies for evoking robust antitumor immunity. From a biochemical perspective, ferroptosis is intricately regulated by multiple cellular metabolic pathways, including iron metabolism, lipid metabolism, redox metabolism, etc., highlighting the importance to elucidate the relationship between tumor metabolism and ferroptosis for developing antitumor therapies. In this review, we provide a comprehensive discussion on the current understanding of ferroptosis-inducing mechanisms and thoroughly discuss the relationship between ferroptosis and various metabolic traits of tumors, which offer promising opportunities for direct tumor inhibition through a nanointegrated approach. Extending from the complex impact of ferroptosis on TIME, we also discussed those important considerations in the development of ferroptosis-based immunotherapy, highlighting the challenges and strategies to enhance the ferroptosis-enabled immunostimulatory effects while avoiding potential side effects. We envision that the insights in this study may facilitate the development and translation of ferroptosis-based nanomedicines for tumor treatment.

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“…Manganese is integral to cGAS-STING signaling, possessing a critical role in antitumor and antiviral immunity [127,128]. Mn 2+ -augmented cGAS-STING signaling has been shown to downregulate the expression level of dihydroorotate dehydrogenase (DHODH), an enzyme implicated in processing mitochondrial ROS and lipid peroxidation, through the production of type I IFNs, ultimately promoting ferroptosis in diverse murine tumor cells [129]. DHODH catalyzes the production of CoQH 2 in the inner mitochondrial membrane, which functions as a radical-trapping antioxidant to impede lipid peroxidation and inhibit ferroptosis [130].…”

Section: Cgas-sting Signaling In Ferroptosismentioning

confidence: 99%

cGAS‐STING signaling in cell death: Mechanisms of action and implications in pathologies

Chen

Liao

et al. 2023

Eur J Immunol

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Cyclic GMP‐AMP synthase (cGAS) monitors dsDNA in the cytosol in response to pathogenic invasion or tissue injury, initiating cGAS‐STING signaling cascades that regulate various cellular physiologies, including IFN /cytokine production, autophagy, protein synthesis, metabolism, senescence, and distinct types of cell death. cGAS‐STING signaling is crucial for host defense and tissue homeostasis; however, its dysfunction frequently leads to infectious, autoimmune, inflammatory, degenerative, and cancerous diseases. Our knowledge regarding the relationships between cGAS‐STING signaling and cell death is rapidly evolving, highlighting their essential roles in pathogenesis and disease progression. Nevertheless, the direct control of cell death by cGAS‐STING signaling, rather than IFN/NF‐κB‐mediated transcriptional regulation, remains relatively unexplored. This review examines the mechanistic interplays between cGAS‐STING cascades and apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic/lysosomal cell death. We will also discuss their pathological implications in human diseases, particularly in autoimmunity, cancer, and organ injury scenarios. We hope that this summary will stimulate discussion for further exploration of the complex life‐or‐death responses to cellular damage mediated by cGAS‐STING signaling.

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

Cited by 36 publications

References 59 publications

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

Ferroptosis Nanomedicine: Clinical Challenges and Opportunities for Modulating Tumor Metabolic and Immunological Landscape

cGAS‐STING signaling in cell death: Mechanisms of action and implications in pathologies

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