1
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Zhou P, Yang G, Wang Y, Peng Y, Xu L, Jiang T, Ma J, Dong W, Chen CP. Development of indole derivatives as inhibitors targeting STING-dependent inflammation. Bioorg Med Chem 2025; 126:118216. [PMID: 40327997 DOI: 10.1016/j.bmc.2025.118216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 04/10/2025] [Accepted: 04/25/2025] [Indexed: 05/08/2025]
Abstract
Constant activation of stimulator of interferon genes (STING), resulting from aberrant metabolism or mutations in STING1, can initiate inflammatory damage or autoimmune disease. STING antagonists have the potential to be used as therapeutics for inflammatory and autoimmune diseases. Based on the structures of the covalent STING inhibitor H151 and C178, we designed, synthesized, and evaluated a novel series of indole derivatives for STING inhibition. Several compounds exhibited efficacious STING inhibitory activity. One of these novel chemical entities, 4dc, was more potent than H151, with IC50 values of 0.14 μM in RAW-LuciaTM ISG cells and 0.39 μM in THP1-Dual™ cells. The compound effectively relieved the symptoms of renal injury in a cisplatin-induced acute kidney injury mouse model. Compound 4dc represents a new chemotype of STING inhibitor that deserves further investigation as anti-inflammatory agent.
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Affiliation(s)
- Peng Zhou
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
| | - Gen Yang
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
| | - Yan Wang
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
| | - Yaya Peng
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
| | - Lingyun Xu
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
| | - Tao Jiang
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
| | - Jinliang Ma
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
| | - Wenpei Dong
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
| | - Chang-Po Chen
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
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2
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Wu K, Xu Y, Liu P, Chen K, Zhao Y. STING inhibitors and degraders: Potential therapeutic agents in inflammatory diseases. Eur J Med Chem 2025; 291:117632. [PMID: 40262301 DOI: 10.1016/j.ejmech.2025.117632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/30/2025] [Accepted: 04/12/2025] [Indexed: 04/24/2025]
Abstract
The regulation of the STING (stimulator of interferon genes) pathway represents a promising target for a range of inflammatory diseases. This review provides an overview of the structure of STING and discusses the mechanisms by which the cyclic GMP-AMP synthase (cGAS)-STING pathway is associated with various autoinflammatory and autoimmune diseases. We explore how targeting STING inhibition or degradation can alleviate excessive inflammatory signaling and improve efficacy. Emerging strategies include inhibiting STING expression by covalently binding compounds or using ligands that target the binding pocket. In addition, selective degradation of STING via the ubiquitin-proteasome system or the lysosomal pathway shows promise. In addition, we explore the implications of modulating the cGAS-STING pathway in the context of various inflammatory diseases. Finally, we summarize the chemical properties of recently developed STING compounds and their potential clinical applications. By comprehensively reviewing the current understanding of the role of STING in inflammation and the therapeutic potential of targeting STING, we aim to identify new avenues of intervention that could improve outcomes for patients with inflammatory diseases. This review highlights the important role of STING in the regulation of inflammation and its potential as a target for innovative therapeutic strategies.
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Affiliation(s)
- Kerong Wu
- Department of General Surgery, Clinical Translational Research Center for Surgical Infection and Immunity of Nanjing Medical University, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yiwen Xu
- Department of General Surgery, Clinical Translational Research Center for Surgical Infection and Immunity of Nanjing Medical University, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Peizhao Liu
- Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
| | - Kexin Chen
- Department of General Surgery, Clinical Translational Research Center for Surgical Infection and Immunity of Nanjing Medical University, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yun Zhao
- Department of General Surgery, Clinical Translational Research Center for Surgical Infection and Immunity of Nanjing Medical University, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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3
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Yang H, Xia Y, Ma Y, Gao M, Hou S, Xu S, Wang Y. Inhibition of the cGAS-STING pathway: contributing to the treatment of cerebral ischemia-reperfusion injury. Neural Regen Res 2025; 20:1900-1918. [PMID: 38993125 PMCID: PMC11691458 DOI: 10.4103/nrr.nrr-d-24-00015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/05/2024] [Accepted: 05/02/2024] [Indexed: 07/13/2024] Open
Abstract
The cGAS-STING pathway plays an important role in ischemia-reperfusion injury in the heart, liver, brain, and kidney, but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed. Here, we outline the components of the cGAS-STING pathway and then analyze its role in autophagy, ferroptosis, cellular pyroptosis, disequilibrium of calcium homeostasis, inflammatory responses, disruption of the blood-brain barrier, microglia transformation, and complement system activation following cerebral ischemia-reperfusion injury. We further analyze the value of cGAS-STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms. Inhibition of the cGAS-STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Hang Yang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Yulei Xia
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Yue Ma
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Mingtong Gao
- Department of Emergency, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Shuai Hou
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Shanshan Xu
- Department of Emergency, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Yanqiang Wang
- Department of Neurology II, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
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4
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Ma R, Fu R, Wang Y, Njobvu KM, Fan Y, Yang Z, Chen M, Liu F, Jiang Z, Rao Y, Huang L, Xu C, Chen J, Liu J. Discovery of novel rigid STING PROTAC degraders as potential therapeutics for acute kidney injury. Eur J Med Chem 2025; 290:117539. [PMID: 40138992 DOI: 10.1016/j.ejmech.2025.117539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Abstract
Acute kidney injury (AKI) is a critical condition resulting from intrinsic immune overactivation for which no ideal therapeutic agent is available. The development of therapeutic drugs with new targets and mechanism has become one of the important challenges in the pharmaceutical field. The interferon gene stimulating protein (STING) directly regulates the intrinsic immune processes and is a potential target for AKI therapy. Herein, we designed synthesized and evaluated a series of novel STING-PROTAC degraders via a rigid strategy. Among them, compound ST9 performed the highest degradation capacity with a DC50 of 0.62 μM in THP-1 cells. In a cisplatin-induced HK-2 cell model, ST9 could down-regulate the STING/NF-κB signaling axis and thus inhibit the expression of inflammatory factors. Additionally, ST9 showed a significantly improved metabolic stability profile. Furthermore, ST9 displayed favorable in vivo anti-AKI efficacy and has no toxic side effects on other organs. These results suggest that the novel rigid STING-PROTAC ST9 has clinical potential as a renoprotective agent for the treatment/prevention of acute kidney injury.
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Affiliation(s)
- Rongxiang Ma
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Renquan Fu
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Yifan Wang
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Kabonde Makasa Njobvu
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Yapeng Fan
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Zichao Yang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China
| | - Mingbing Chen
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Feifei Liu
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Zhongping Jiang
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Yong Rao
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Ling Huang
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Congjun Xu
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
| | - Jianjun Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
| | - Jin Liu
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
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5
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Luo H, Cai Y, Shi H, Ma L, Zhang S, Yung KKL, Zhou P. Repurposing oxiconazole to inhibit STING trafficking via OSBP and alleviate autoimmune pathology in Trex1 -/- mice. Int Immunopharmacol 2025; 157:114742. [PMID: 40319749 DOI: 10.1016/j.intimp.2025.114742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
The cGAS-STING pathway is a critical component of the innate immune response to cytosolic DNA, driving the production of type I interferons (IFNs) and pro-inflammatory cytokines. However, excessive activation of this pathway is associated with various autoimmune and inflammatory diseases. In this study, we evaluated the regulation of FDA-approved azole antifungal drugs on the cGAS-STING pathway. Among these drugs, oxiconazole, miconazole, and itraconazole demonstrate significant inhibitory effects, with oxiconazole showing the strongest activity. Our data demonstrates that oxiconazole significantly suppressed type I IFN production and downstream inflammatory responses in macrophages and fibroblasts stimulated with synthetic DNA or infected with HSV-1. Mechanistically, oxiconazole hindered STING trafficking via oxysterol-binding protein OSBP. Using the Listeria monocytogenes infection model and the Trex1-/- mouse disease model, both representing in vivo models of inflammation driven by excessive cGAS-STING activation, we demonstrate that oxiconazole enhanced bacterial clearance and reduced tissue damage in the Listeria monocytogenes infection model. Moreover, oxiconazole treatment significantly alleviated multi-organ inflammation and normalized aberrant IFN responses in the Trex1-/- autoimmune disease mouse model. These findings highlight the potential of oxiconazole as a promising therapeutic agent for STING-driven autoimmune and inflammatory diseases.
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Affiliation(s)
- Hui Luo
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yijing Cai
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hanhui Shi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Liang Ma
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shiqing Zhang
- JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Ken Kin Lam Yung
- Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, Department of Science and Environmental Studies, the Education University of Hong Kong, Hong Kong, SAR 999077, China
| | - Pingzheng Zhou
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China.
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6
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Zhao HY, Zhang L, Liu Z, He M, Wang M, Li Q, Sarkari F, Tao J, Wen B, Basrur V, Myatt H, Nesvizhskii A, Sun D. Design of Potent Small-Molecule Stimulator of Interferon Gene Inhibitor and Stimulator of Interferon Gene Mutant-Specific Degrader. J Med Chem 2025. [PMID: 40386971 DOI: 10.1021/acs.jmedchem.5c00123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Stimulator of interferon genes (STING) is involved in various autoimmune diseases. However, it is challenging to develop small-molecule STING inhibitors with potent activity. Herein, we designed a small-molecule STING inhibitor and STING mutant-specific degrader by binding two coupled pockets of a STING dimer. Structure optimization selected SI-24, SI-42, and SI-43 with low nanomolar activity to inhibit 2'3'-cyclic GMP-AMP (cGAMP)-induced STING activation and release of IFN-β and CXCL-10, which were far more potent than reported STING inhibitors. Moreover, the three lead compounds suppressed cGAMP-induced oligomerization of STING and phosphorylation of interferon regulatory factor 3 (IRF3) and STING. Surprisingly, SI-43 promoted mutant-specific and proteasome-independent degradation of STINGS154 and STINGM155. Subcutaneous or oral administration of SI-24, SI-42, and SI-43 reduced serum IFN-β and CXCL-10 in the cGAMP-induced autoimmune disease mouse model. Our dual-functional compounds provide a new strategy to investigate STING function through both inhibition and mutant-specific degradation in autoimmune diseases.
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Affiliation(s)
- Hong-Yi Zhao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Luchen Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Zhongwei Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Miao He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Meilin Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Qiuxia Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Farzad Sarkari
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Jinsong Tao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Venkatesha Basrur
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Hannah Myatt
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Alexey Nesvizhskii
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
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7
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An Y, Zhang Y, Luo X, Lan Y, Geng M, Duan W, Xie Z, Zhang H. Discovery of indole derivatives as STING degraders. Eur J Med Chem 2025; 294:117747. [PMID: 40398154 DOI: 10.1016/j.ejmech.2025.117747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/23/2025]
Abstract
Aberrant activation of the stimulator of interferon genes (STING) pathway is associated with the development of various inflammatory and autoimmune diseases. Targeting STING for degradation represents a novel strategy for the treatment of these diseases. In this study, we designed and synthesized a series of STING-PROTACs based on a nitro-free covalent warhead and different E3 ligase binders. The representative compound 2h specifically degraded STING protein through the proteasome pathway with a DC50 value of 3.23 μM and exhibited sustained degradation activity over 72 h. Further biological studies demonstrated that compound 2h inhibited STING signaling and effectively suppressed immune-inflammatory cytokines both in vitro and in vivo. Moreover, compound 2h offered better safety compared to its warhead molecule and SP23. Collectively, compound 2h is a potent nitro-free covalent STING degrader and warrants further investigation.
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Affiliation(s)
- Yuxiang An
- Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Yan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China
| | - Xin Luo
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, Jiangsu, 210023, China
| | - Yaohan Lan
- Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Meiyu Geng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, Jiangsu, 210023, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China
| | - Wenhu Duan
- Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Zuoquan Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
| | - Hefeng Zhang
- Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
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8
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Kumar A, Kumar G, Kalia N, Sahoo PR. Design and synthetic approaches to thalidomide based small molecule degraders. Eur J Med Chem 2025; 293:117700. [PMID: 40367675 DOI: 10.1016/j.ejmech.2025.117700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/13/2025] [Accepted: 04/27/2025] [Indexed: 05/16/2025]
Abstract
Thalidomide has been used as a repurposed drug for treating multiple myeloma since 1997. Several novel anticancer drugs containing thalidomide active moiety has been discovered since then. Many thalidomide drug candidates with tuned linker size have been instrumental in inhibiting histone deacetylase, kinase, transcription factors etc. and facilitate selective degradation of E3 ligase and other enzymes. Here we are focused on small molecule degraders that are being tailored with tweaking synthetic architectures around thalidomide chemical motif towards the development of promising drug candidates. Interesting biomedical applications of thalidomide-based degraders with recent developments including pharmacokinetic profiles, protein stability, activity studies, degradation assays, and antitumor response are elucidated.
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Affiliation(s)
- Ajeet Kumar
- Department of Chemistry, University of Florida, Gainesville, FL, 32611, United States
| | - Gulshan Kumar
- Amity Institute of Pharmacy, Amity University Haryana, Manesar, 122413, India
| | - Nidhi Kalia
- Department of Chemistry, University of Florida, Gainesville, FL, 32611, United States
| | - Priya Ranjan Sahoo
- Department of Chemistry, University at Buffalo, The State University of New York, Amherst, NY, 14260, United States; Department of Chemistry, University of Delhi, Delhi, 110007, India.
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9
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Zhang M, Wu C, Lu D, Wang X, Shang G. cGAS-STING: mechanisms and therapeutic opportunities. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1309-1323. [PMID: 39821837 DOI: 10.1007/s11427-024-2808-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/04/2024] [Indexed: 01/19/2025]
Abstract
The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA (dsDNA) in the cytoplasm and triggering downstream signal transduction. Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway. This review provides a detailed examination of the structural features of cGAS and STING proteins, with a particular emphasis on their activation and inhibition mechanisms. We also discuss the novel discovery of STING functioning as an ion channel. Furthermore, we offer an overview of key agonists and antagonists of cGAS and STING, shedding light on their mechanisms of action. Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.
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Affiliation(s)
- Mengyuan Zhang
- Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, China
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, 030001, China
| | - Changxin Wu
- The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Defen Lu
- College of Life Sciences, Shanxi Agricultural University, Taiyuan, 030031, China.
| | - Xing Wang
- Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, China.
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, 030001, China.
| | - Guijun Shang
- The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
- College of Life Sciences, Shanxi Agricultural University, Taiyuan, 030031, China.
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10
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Wang SY, Chen YS, Jin BY, Bilal A. The cGAS-STING pathway in atherosclerosis. Front Cardiovasc Med 2025; 12:1550930. [PMID: 40351606 PMCID: PMC12062000 DOI: 10.3389/fcvm.2025.1550930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 04/09/2025] [Indexed: 05/14/2025] Open
Abstract
Atherosclerosis (AS), a chronic inflammatory disease, remains a leading contributor to cardiovascular morbidity and mortality. Recent studies highlight the critical role of the cGAS-STING pathway-a key innate immune signaling cascade-in driving AS progression. This pathway is activated by cytoplasmic DNA from damaged cells, thereby triggering inflammation and accelerating plaque formation. While risk factors such as aging, obesity, smoking, hypertension, and diabetes are known to exacerbate AS, emerging evidence suggests that these factors may also enhance cGAS-STING pathway, which amplifies inflammatory responses. Targeting this pathway offers a promising therapeutic strategy to reduce the burden of cardiovascular diseases (CVD). In this review, we summarize the mechanisms of the cGAS-STING pathway, explore its role in AS, and evaluate potential inhibitors as future therapeutic candidates. By integrating current knowledge, we aim to provide insights for developing novel treatments to mitigate AS and CVD burden.
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Affiliation(s)
- Si-yu Wang
- Department of Cardiology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yu-shan Chen
- Department of Cardiology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
- Heart Center/National Regional (Traditional Chinese Medicine) Cardiovascular Diagnosis and Treatment Center, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Bo-yuan Jin
- Department of Cardiology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Ahmad Bilal
- Department of Cardiology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
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11
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Shen A, Wang X, Chen Q, Zhang Y, Wang F, Li Y, Liu Z, Deng L, Ouyang W, Geng M, Song Z, Xie Z, Zhang A. Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents. J Med Chem 2025; 68:8907-8932. [PMID: 40188441 DOI: 10.1021/acs.jmedchem.5c00580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2025]
Abstract
Given the critical role of STING in autoimmune and inflammatory disorders, the development of targeted small-molecule inhibitors has been a promising strategy for the treatment of these diseases. Nevertheless, the currently reported STING inhibitors suffer from limited structural diversity, species sensitivity, and poor activity; therefore, none are suitable for clinical investigation. Herein, we performed a structural modification campaign on the tool compound 6 (H-151) based on its potential metabolic hotspots. Compound 66, bearing a difluorobenzodioxol moiety, was identified as one of the most potent STING inhibitors with IC50 values of 116 and 96.3 nM for h- and m-STING, respectively. This compound exhibited a notable enhancement in metabolic properties, especially in terms of metabolic stability. A mechanism study verified that 66 engaged with STING in a covalent manner akin to that of 6. In both the cisplatin-induced acute kidney injury and TREX1 D18N mouse models, 66 significantly alleviated tissue injury and inflammation.
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Affiliation(s)
- Ancheng Shen
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiyuan Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qingxuan Chen
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
| | - Yan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Fang Wang
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yuqiang Li
- Shanghai Artificial Intelligence Laboratory, Shanghai 200433, China
| | - Zhiguo Liu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Liufu Deng
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
| | - Wanli Ouyang
- Shanghai Artificial Intelligence Laboratory, Shanghai 200433, China
| | - Meiyu Geng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Zilan Song
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
| | - Zuoquan Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ao Zhang
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
- Shanghai Artificial Intelligence Laboratory, Shanghai 200433, China
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
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12
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Chen X, Zhuo SH, Li YM. Oligomerization of STING and Chemical Regulatory Strategies. Chembiochem 2025; 26:e202400888. [PMID: 39900536 DOI: 10.1002/cbic.202400888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/05/2025]
Abstract
Stimulator of interferon genes (STING) plays a crucial role in innate immunity. Upon the recognition of cytosolic dsDNA, STING undergoes several structural changes, with oligomerization playing a key role in initiating a cascade of immune responses. Therefore, controlling the STING pathway by manipulating STING oligomerization is a practical strategy. This review focuses on the detailed mechanism of STING oligomerization, highlighting its decisive role. It also describes oligomerization-based strategies to regulate STING protein, such as the use of small-molecule agonists and biomacromolecules, highlighting their interaction modes and potential therapeutic applications. This knowledge may lead to the development of innovative approaches for treating cancer and immune disorders.
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Affiliation(s)
- Xi Chen
- Zhili College, Tsinghua University, Beijing, 100084, P. R. China
| | - Shao-Hua Zhuo
- Department of Chemistry, Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, P. R. China
| | - Yan-Mei Li
- Department of Chemistry, Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, P. R. China
- Beijing Institute for Brain Disorders, Beijing, 100084, P. R. China
- Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, P. R. China
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13
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Wang S, Qin L, Liu F, Zhang Z. Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies. Cell Commun Signal 2025; 23:171. [PMID: 40197235 PMCID: PMC11977922 DOI: 10.1186/s12964-025-02169-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/23/2025] [Indexed: 04/10/2025] Open
Abstract
The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.
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Affiliation(s)
- Siwei Wang
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Qin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology), Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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14
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Gao F, Zheng Z, Liu X, Li J. CMPK2 promotes microglial activation through the cGAS-STING pathway in the neuroinflammatory mechanism. Sci Rep 2025; 15:11807. [PMID: 40189684 PMCID: PMC11973145 DOI: 10.1038/s41598-025-97232-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 04/03/2025] [Indexed: 04/09/2025] Open
Abstract
The activation of microglia and the resulting neuroinflammation play crucial regulatory roles in the pathogenesis and progression of neurological diseases, although the specific mechanisms remain incompletely understood. Cytidine monophosphate kinase 2 (CMPK2) is a key mitochondrial nucleotide kinase involved in cellular energy metabolism and nucleotide synthesis. Recent studies suggest that CMPK2 plays a role in microglial-mediated neuroinflammation; however, its specific impact on microglial activation remains unclear. In this study, we hypothesize that CMPK2 promotes microglial-mediated neuroinflammation by activating the cGAS-STING signaling pathway. To investigate this mechanism, we employed lipopolysaccharide (LPS)-treated microglial cells to investigate the detailed mechanisms by which CMPK2 regulates neuroinflammation. Our experimental results indicate that in the BV2 and mouse primary microglial neuroinflammation model, both CMPK2 protein and transcript levels were significantly elevated, accompanied by microglial activation phenotypes such as increased cell size, shortened processes, transformation to round or rod-like shapes, and elevated CD40 expression. Concurrently, there was an increase in pro-inflammatory cytokine levels and a decrease in anti-inflammatory cytokine levels. Further investigation revealed that in the microglial, the expression of cGAS and STING was elevated, along with an increase in oxidative products and inflammatory responses. CMA stimulation further intensified these changes, while cGAS knockdown mitigated them. Finally, we demonstrated that cGAS knockdown inhibited the oxidative stress, cell activation-related changes, and neuroinflammatory responses induced by CMPK2 overexpression in the BV2 neuroinflammation model. Molecular docking experiments showed that CMPK2 stably binds to cGAS at the protein level. These findings suggest that the cGAS-STING pathway mediates CMPK2-induced microglial activation. In summary, our study demonstrates that LPS-induced CMPK2 overactivity promotes microglial activation and neuroinflammatory through the cGAS-STING pathway.
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Affiliation(s)
- Feng Gao
- Department of Neurosurgery, Xingtai People's Hospital, Xingtai, Hebei, China.
| | - Zijian Zheng
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
| | - Xinjie Liu
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jianwei Li
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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15
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Mu W, Xu G, Li L, Wen J, Xiu Y, Zhao J, Liu T, Wei Z, Luo W, Yang H, Wu Z, Zhan X, Xiao X, Bai Z. Carnosic Acid Directly Targets STING C-Terminal Tail to Improve STING-Mediated Inflammatory Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2417686. [PMID: 39965124 PMCID: PMC11984877 DOI: 10.1002/advs.202417686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/30/2025] [Indexed: 02/20/2025]
Abstract
cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling plays a vital role in innate immunity, while its deregulation may lead to a wide variety of autoinflammatory and autoimmune diseases. It is essential to identify specifically effective lead compounds to inhibit the signaling. Herein, it is shown that carnosic acid (CA), an active ingredient of medicinal plant Rosmarinus officinalis L., specifically suppressed cGAS-STING pathway activation and the subsequent inflammatory responses. Mechanistically, CA directly bound to STING C-terminal tail (CTT), impeded the recruitment of TANK-binding kinase 1 (TBK1) onto STING signalosome, thereby blocking the phosphorylation of STING and interferon regulatory factor 3 (IRF3) nuclear translocation. Importantly, CA dramatically attenuated STING-mediated inflammatory responses in vivo. Consistently, CA has a salient ameliorative effect on autoinflammatory disease model mediated by Trex1 deficiency, via inhibition of the cGAS-STING signaling. Notably, the study further indicates that phenolic hydroxyl groups are essential for CA-mediated STING inhibitory activity. Collectively, the results thus identify STING as one of the crucial targets of CA for mediating CA's anti-inflammatory activity, and further reveal that STING CTT may be a novel promising target for drug development.
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Affiliation(s)
- Wenqing Mu
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- School of Traditional Chinese MedicineCapital Medical UniversityBeijing100069China
- State Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSoochow UniversityJiangsu215123China
| | - Guang Xu
- School of Traditional Chinese MedicineCapital Medical UniversityBeijing100069China
| | - Ling Li
- Beijing Institute of BiotechnologyBeijing100071China
| | - Jincai Wen
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Ye Xiu
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Jia Zhao
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Tingting Liu
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Ziying Wei
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Wei Luo
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Huijie Yang
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Zhixin Wu
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Xiaoyan Zhan
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Xiaohe Xiao
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
| | - Zhaofang Bai
- Department of Hepatologythe Fifth Medical Center of PLA General HospitalBeijing100039China
- Military Institute of Chinese MateriaFifth Medical Center of Chinese PLA General HospitalBeijing100039China
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16
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Steglich M, Larrieux N, Zeida A, Dalla Rizza J, Salvatore SR, Bonilla M, Möller MN, Buschiazzo A, Alvarez B, Schopfer FJ, Turell L. Human glutathione transferases catalyze the reaction between glutathione and nitrooleic acid. J Biol Chem 2025; 301:108362. [PMID: 40024478 PMCID: PMC11999266 DOI: 10.1016/j.jbc.2025.108362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
Nitroalkene fatty acids (NO2-FAs) are formed endogenously. They regulate cell signaling pathways and are being developed clinically to treat inflammatory diseases. NO2-FAs are electrophilic and form thioether adducts with glutathione (GSH), which are exported from cells. Glutathione transferases (GSTs), a superfamily of enzymes, contribute to the cellular detoxification of hydrophobic electrophiles by catalyzing their conjugation to GSH. Herein, we evaluated the capacity of five human GSTs (M1-1, M2-2, M4-4, A4-4, and P1-1) to catalyze the reaction between nitrooleic acid (NO2-OA) and GSH. The reaction was monitored by HPLC-ESI-MS/MS, and catalytic activity was detected with hGSTs M1-1 and A4-4. Using stopped-flow spectrophotometry, a 1400- and 7500-fold increase in the apparent second-order rate constant was observed for hGST M1-1 and hGST A4-4, respectively, compared to the uncatalyzed reaction (pH 7.4, 25 °C). The acceleration was in part due to a higher availability of the thiolate. The crystal structure of hGST M1-1 in complex with the adduct was solved at 2.55 Å resolution, revealing that the ligand was bound within the active site, and establishing a foundation to build a model of hGST A4-4 in complex with the adduct. A larger number of interactions between the enzyme and the fatty acid were observed for hGST A4-4 compared to hGST M1-1, probably contributing to the increased catalysis. Altogether, these results show, for the first time, that hGSTs can catalyze the reaction between GSH and NO2-FAs, likely affecting the signaling actions of these metabolites and expanding the repertoire of GST substrates.
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Affiliation(s)
- Martina Steglich
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay; Graduate Program in Chemistry, Facultad de Química, Universidad de la República, Montevideo, Uruguay
| | - Nicole Larrieux
- Unidad de Cristalografía de Proteínas, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Ari Zeida
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay; Facultad de Medicina, Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay
| | - Joaquín Dalla Rizza
- Unidad de Cristalografía de Proteínas, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Sonia R Salvatore
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - Mariana Bonilla
- Laboratorio de Biología Redox de Tripanosomas, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Matías N Möller
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay; Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Alejandro Buschiazzo
- Unidad de Cristalografía de Proteínas, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Beatriz Alvarez
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Francisco J Schopfer
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Lucía Turell
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
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17
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Zhang Z, Wei X, Huang Q, Shi Z, Chen X, Wu J, Wang X, Li J, Gou L, Yang J. Discovery of STING antagonists targeting cGAS-STING pathway to alleviate IMQ-induced psoriasis-like dermatitis. Eur J Pharm Sci 2025; 210:107091. [PMID: 40174660 DOI: 10.1016/j.ejps.2025.107091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/04/2025]
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is pivotal in the immune defense against infections and cancer. However, aberrant activation of this pathway can trigger autoimmune and inflammatory diseases by inducing excessive production of type I interferon (IFN) and pro-inflammatory cytokines. Inhibition of the aberrant activation of the cGAS-STING signaling pathway by targeting STING represents a novel therapeutic strategy for these autoimmune and inflammatory disorders. In this study, we discovered three novel STING antagonists based on surface plasmon resonance (SPR), differential scanning fluorimetry (DSF), and ISRE (interferon stimulated response element)-luciferase assays. The efficacy and pharmacological mechanisms of the three STING antagonists for treating imiquimod (IMQ)-induced psoriasis-like dermatitis by western blotting (WB), flow fluorescence, and immunostaining. The three STING antagonists exhibited pan-inhibitory activities on the activation of both the human and mouse cGAS-STING signaling pathway. Intravenous and topical administration of the three antagonists alleviated the inflammation and skin lesions associated with IMQ-induced psoriasis-like dermatitis via suppression of the inflammatory cascade mediated by the IMQ-TLR-7-NF-κB/cGAS-STING-NF-κB/IL-1β-IL-1R-NF-κB/TNFα-TNF-R-NF-κB signaling axis. In conclusion, we identified three novel STING antagonists with pan-inhibitory activities against human and mouse STING, providing lead compounds for the future development of both STING antagonists and immune agents for therapeutically manipulating STING-driven diseases, such as psoriasis. Our findings offer another new therapeutic strategy for managing STING-driven autoimmune and inflammatory diseases, while also reemphasizing the critical role of the cGAS-STING signaling pathway in such conditions.
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Affiliation(s)
- Zhixiong Zhang
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Xian Wei
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Qiang Huang
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Zhonghua Shi
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Xiaofeng Chen
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Jialin Wu
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Xin Wang
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Jiaqi Li
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Lantu Gou
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Jinliang Yang
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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18
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Niu GH, Hsiao WC, Lee PH, Zheng LG, Yang YS, Huang WC, Hsieh CC, Chiu TY, Wang JY, Chen CP, Huang CL, You MS, Kuo YP, Wang CM, Wen ZH, Yu GY, Chen CT, Chi YH, Tung CW, Hsu SC, Yeh TK, Sung PJ, Zhang MM, Tsou LK. Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid. J Med Chem 2025; 68:5471-5487. [PMID: 40014799 PMCID: PMC11912488 DOI: 10.1021/acs.jmedchem.4c02665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/16/2025] [Accepted: 02/20/2025] [Indexed: 03/01/2025]
Abstract
Pharmacological inhibition of the cGAS-STING-controlled innate immune pathway is an emerging therapeutic strategy for a myriad of inflammatory diseases. Here, we report GHN105 as an orally bioavailable covalent STING inhibitor. Late-stage diversification of the briarane-type diterpenoid excavatolide B allowed the installation of solubility-enhancing functional groups while enhancing its activity as a covalent STING inhibitor against multiple human STING variants, including the S154 variant responsible for a genetic autoimmune disease. Selectively engaging the membrane-proximal Cys91 residue of STING, GHN105 dose-dependently inhibited cGAS-STING signaling and type I interferon responses in cells and in vivo. Moreover, orally administered GHN105 exhibited on-target engagement in vivo and markedly reversed key pathological features in a delayed treatment of the acute colitis mouse model. Our study provided proof of concept that the synthetic briarane analog GHN105 serves as a safe, site-selective, and orally active covalent STING inhibitor and devises a regimen that allows long-term systemic administration.
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Affiliation(s)
- Guang-Hao Niu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Wan-Chi Hsiao
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Po-Hsun Lee
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Li-Guo Zheng
- National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan
| | - Yu-Shao Yang
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Wei-Cheng Huang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Chih-Chien Hsieh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Tai-Yu Chiu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Jing-Ya Wang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Ching-Ping Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Chen-Lung Huang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - May-Su You
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Yi-Ping Kuo
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Chien-Ming Wang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan
| | - Guann-Yi Yu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Chiung-Tong Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Ya-Hui Chi
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Chun-Wei Tung
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Shu-Ching Hsu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Teng-Kuang Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Ping-Jyun Sung
- National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan
| | - Mingzi M Zhang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
| | - Lun Kelvin Tsou
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
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19
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Quan S, Fu X, Cai H, Ren Z, Xu Y, Jia L. The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease. Mol Neurodegener 2025; 20:25. [PMID: 40038765 PMCID: PMC11877805 DOI: 10.1186/s13024-025-00815-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 02/17/2025] [Indexed: 03/06/2025] Open
Abstract
The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates in AD-related neuroinflammation and neurodegeneration. A substantial body of evidence indicates that mitochondria are involved in the critical pathogenic mechanisms of AD, whose damage leads to the release of mitochondrial DNA (mtDNA) into the extramitochondrial space. This leaked mtDNA serves as a DAMP, activating various pattern recognition receptors and immune defense networks in the brain, including the cGAS-STING pathway, ultimately leading to an imbalance in immune homeostasis. Therefore, modulation of the mtDNA-cGAS-STING pathway to restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In this review, we focus on the mechanisms of mtDNA release during stress and the activation of the cGAS-STING pathway. Additionally, we delve into the research progress on this pathway in AD, and further discuss the primary directions and potential hurdles in developing targeted therapeutic drugs, to gain a deeper understanding of the pathogenesis of AD and provide new approaches for its therapy.
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Affiliation(s)
- Shuiyue Quan
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100053, China
| | - Xiaofeng Fu
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100053, China
| | - Huimin Cai
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100053, China
| | - Ziye Ren
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100053, China
| | - Yinghao Xu
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100053, China
| | - Longfei Jia
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100053, China.
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20
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Improving the safety of lipid nanoparticle-based DNA delivery for extended gene expression. Nat Biotechnol 2025:10.1038/s41587-025-02600-4. [PMID: 40033053 DOI: 10.1038/s41587-025-02600-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
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21
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Li X, Hu X, You H, Zheng K, Tang R, Kong F. Regulation of pattern recognition receptor signaling by palmitoylation. iScience 2025; 28:111667. [PMID: 39877903 PMCID: PMC11772949 DOI: 10.1016/j.isci.2024.111667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025] Open
Abstract
Pattern recognition receptors (PRRs), consisting of Toll-like receptors, RIG-I-like receptors, cytosolic DNA sensors, and NOD-like receptors, sense exogenous pathogenic molecules and endogenous damage signals to maintain physiological homeostasis. Upon activation, PRRs stimulate the sensitization of nuclear factor κB, mitogen-activated protein kinase, TANK-binding kinase 1-interferon (IFN) regulatory factor, and inflammasome signaling pathways to produce inflammatory factors and IFNs to activate Janus kinase/signal transducer and activator of transcription signaling pathways, resulting in anti-infection, antitumor, and other specific immune responses. Palmitoylation is a crucial type of post-translational modification that reversibly alters the localization, stability, and biological activity of target molecules. Here, we discuss the available knowledge on the biological roles and underlying mechanisms linked to protein palmitoylation in modulating PRRs and their downstream signaling pathways under physiological and pathological conditions. Moreover, recent advances in the use of palmitoylation as an attractive therapeutic target for disorders caused by the dysregulation of PRRs were summarized.
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Affiliation(s)
- Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaofang Hu
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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22
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Nie AY, Xiao ZH, Deng JL, Li N, Hao LY, Li SH, Hu XY. Bidirectional regulation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon gene pathway and its impact on hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:98556. [PMID: 39958554 PMCID: PMC11755995 DOI: 10.4251/wjgo.v17.i2.98556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/30/2024] [Accepted: 11/18/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths in China, and the treatment options are limited. The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activates the stimulator of interferon gene (STING) signaling pathway as a crucial immune response pathway in the cytoplasm, which detects cytoplasmic DNA to regulate innate and adaptive immune responses. As a potential therapeutic target, cGAS-STING pathway markedly inhibits tumor cell proliferation and metastasis, with its activation being particularly relevant in HCC. However, prolonged pathway activation may lead to an immunosuppressive tumor microenvironment, which fostering the invasion or metastasis of liver tumor cells. AIM To investigate the dual-regulation mechanism of cGAS-STING in HCC. METHODS This review was conducted according to the PRISMA guidelines. The study conducted a comprehensive search for articles related to HCC on PubMed and Web of Science databases. Through rigorous screening and meticulous analysis of the retrieved literature, the research aimed to summarize and elucidate the impact of the cGAS-STING pathway on HCC tumors. RESULTS All authors collaboratively selected studies for inclusion, extracted data, and the initial search of online databases yielded 1445 studies. After removing duplicates, the remaining 964 records were screened. Ultimately, 55 articles met the inclusion criteria and were included in this review. CONCLUSION Acute inflammation can have a few inhibitory effects on cancer, while chronic inflammation generally promotes its progression. Extended cGAS-STING pathway activation will result in a suppressive tumor microenvironment.
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Affiliation(s)
- Ai-Yu Nie
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Zhong-Hui Xiao
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Jia-Li Deng
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Na Li
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Li-Yuan Hao
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Sheng-Hao Li
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Xiao-Yu Hu
- Department of Infection, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
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23
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Yu H, Ren K, Jin Y, Zhang L, Liu H, Huang Z, Zhang Z, Chen X, Yang Y, Wei Z. Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis. Neuropharmacology 2025; 264:110217. [PMID: 39557152 DOI: 10.1016/j.neuropharm.2024.110217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/02/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.
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Affiliation(s)
- Haihan Yu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Kaidi Ren
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Yage Jin
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Li Zhang
- Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Hui Liu
- Henan Key Laboratory of Immunology and Targeted Drug, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Zhen Huang
- Henan Key Laboratory of Immunology and Targeted Drug, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Ziheng Zhang
- College of Life Sciences, Xinjiang University, Urumqi, Xinjiang, 830046, PR China
| | - Xing Chen
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
| | - Yang Yang
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
| | - Ziqing Wei
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
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24
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Han X, Ma G, Peng R, Xu J, Sheng L, Liu H, Sui Q, Li J, Gu Y, Yu J, Feng Z, Xu Q, Wen X, Yuan H, Sun H, Dai L. Discovery of an Orally Bioavailable STING Inhibitor with In Vivo Anti-Inflammatory Activity in Mice with STING-Mediated Inflammation. J Med Chem 2025; 68:2963-2980. [PMID: 39875322 DOI: 10.1021/acs.jmedchem.4c02200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway plays a key role in triggering interferon and inflammatory responses against microbial invasion or tumor. However, aberrant activation of the cGAS-STING pathway is associated with a variety of inflammatory and autoimmune diseases, and thus inhibition of STING is regarded as a potential new approach to treating these diseases. Herein, we report a series of novel indolyl-urea derivatives as STING inhibitors. The representative compound 42 exhibited potent STING inhibitory activity, acceptable pharmacokinetic properties, and good in vivo safety profiles. Mechanistically, 42 could block the palmitoylation of the STING protein and STING downstream signaling. Importantly, oral administration of 42 could effectively suppress STING-mediated inflammation in 10-carboxymethyl-9-acridanone (CMA)-treated mouse and Trex1-/- mouse. Together, compound 42 represents a promising STING inhibitor for treating STING-associated inflammatory and autoimmune diseases.
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Affiliation(s)
- Xi Han
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Guangcai Ma
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ruikun Peng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China
| | - Ju Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Lixin Sheng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Haohao Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Qibang Sui
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Jiaxin Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China
| | - Yuhao Gu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Jinli Yu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zhiqi Feng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China
| | - Qinglong Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoan Wen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China
| | - Haoliang Yuan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Hongbin Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China
| | - Liang Dai
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China
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25
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Patel MN, Tiwari S, Wang Y, O'Neill S, Wu J, Omo-Lamai S, Espy C, Chase LS, Majumder A, Hoffman E, Shah A, Sárközy A, Katzen J, Pardi N, Brenner JS. Safer non-viral DNA delivery using lipid nanoparticles loaded with endogenous anti-inflammatory lipids. Nat Biotechnol 2025:10.1038/s41587-025-02556-5. [PMID: 39910195 DOI: 10.1038/s41587-025-02556-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 01/08/2025] [Indexed: 02/07/2025]
Abstract
The value of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA) was demonstrated by the coronavirus disease 2019 (COVID-19) mRNA vaccines, but the ability to use LNPs to deliver plasmid DNA (pDNA) would provide additional advantages, such as longer-term expression and availability of promoter sequences. However, pDNA-LNPs face substantial challenges, such as toxicity and low delivery efficiency. Here we show that pDNA-LNPs induce acute inflammation in naive mice that is primarily driven by the cGAS-STING pathway. Inspired by DNA viruses that inhibit this pathway for replication, we loaded endogenous lipids that inhibit STING into pDNA-LNPs. Loading nitro-oleic acid (NOA) into pDNA-LNPs (NOA-pDNA-LNPs) ameliorated serious inflammatory responses in vivo, enabling safer, prolonged transgene expression-11.5 times greater than that of mRNA-LNPs at day 32. Additionally, we performed a small LNP formulation screen to iteratively optimize transgene expression and increase expression 50-fold in vitro. pDNA-LNPs loaded with NOA and other bioactive molecules should advance genetic medicine by enabling longer-term and promoter-controlled transgene expression.
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Affiliation(s)
- Manthan N Patel
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Sachchidanand Tiwari
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Yufei Wang
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Sarah O'Neill
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Jichuan Wu
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Serena Omo-Lamai
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
- Department of Bioengineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - Carolann Espy
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Liam S Chase
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
- Department of Bioengineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - Aparajeeta Majumder
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Evan Hoffman
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Anit Shah
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - András Sárközy
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeremy Katzen
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
| | - Norbert Pardi
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jacob S Brenner
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA.
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26
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Kalinkovich A, Livshits G. The cross-talk between the cGAS-STING signaling pathway and chronic inflammation in the development of musculoskeletal disorders. Ageing Res Rev 2025; 104:102602. [PMID: 39612990 DOI: 10.1016/j.arr.2024.102602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/18/2024] [Accepted: 11/25/2024] [Indexed: 12/01/2024]
Abstract
Musculoskeletal disorders (MSDs) comprise diverse conditions affecting bones, joints, and muscles, leading to pain and loss of function, and are one of the most prevalent and major global health concerns. One of the hallmarks of MSDs is DNA damage. Once accumulated in the cytoplasm, the damaged DNA is sensed by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, which triggers the induction of type I interferons and inflammatory cytokines. Thus, this pathway connects the musculoskeletal and immune systems. Inhibitors of cGAS or STING have shown promising therapeutic effects in the pre-clinical models of several MSDs. Systemic, chronic, low-grade inflammation (SCLGI) underlies the development and maintenance of many MSDs. Failure to resolve SCLGI has been hypothesized to play a critical role in the development of chronic diseases, suggesting that the successful resolution of SCLGI will result in the alleviation of their related symptomatology. The process of inflammation resolution is feasible by specialized pro-resolving mediators (SPMs), which are enzymatically generated from dietary essential polyunsaturated fatty acids (PUFAs). The supplementation of SPMs or their stable, small-molecule mimetics and receptor agonists has revealed beneficial effects in inflammation-related animal models, including arthropathies, osteoporosis, and muscle dystrophy, suggesting a translational potential in MSDs. In this review, we substantiate the hypothesis that the use of cGAS-STING signaling pathway inhibitors together with SCLG-resolving compounds may serve as a promising new therapeutic approach for MSDs.
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Affiliation(s)
- Alexander Kalinkovich
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv 6905126, Israel
| | - Gregory Livshits
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv 6905126, Israel; Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel.
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27
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Revol-Cavalier J, Quaranta A, Newman JW, Brash AR, Hamberg M, Wheelock CE. The Octadecanoids: Synthesis and Bioactivity of 18-Carbon Oxygenated Fatty Acids in Mammals, Bacteria, and Fungi. Chem Rev 2025; 125:1-90. [PMID: 39680864 PMCID: PMC11719350 DOI: 10.1021/acs.chemrev.3c00520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/06/2024] [Accepted: 11/15/2024] [Indexed: 12/18/2024]
Abstract
The octadecanoids are a broad class of lipids consisting of the oxygenated products of 18-carbon fatty acids. Originally referring to production of the phytohormone jasmonic acid, the octadecanoid pathway has been expanded to include products of all 18-carbon fatty acids. Octadecanoids are formed biosynthetically in mammals via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) activity, as well as nonenzymatically by photo- and autoxidation mechanisms. While octadecanoids are well-known mediators in plants, their role in the regulation of mammalian biological processes has been generally neglected. However, there have been significant advancements in recognizing the importance of these compounds in mammals and their involvement in the mediation of inflammation, nociception, and cell proliferation, as well as in immuno- and tissue modulation, coagulation processes, hormone regulation, and skin barrier formation. More recently, the gut microbiome has been shown to be a significant source of octadecanoid biosynthesis, providing additional biosynthetic routes including hydratase activity (e.g., CLA-HY, FA-HY1, FA-HY2). In this review, we summarize the current field of octadecanoids, propose standardized nomenclature, provide details of octadecanoid preparation and measurement, summarize the phase-I metabolic pathway of octadecanoid formation in mammals, bacteria, and fungi, and describe their biological activity in relation to mammalian pathophysiology as well as their potential use as biomarkers of health and disease.
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Affiliation(s)
- Johanna Revol-Cavalier
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Larodan
Research Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - Alessandro Quaranta
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - John W. Newman
- Western
Human Nutrition Research Center, Agricultural
Research Service, USDA, Davis, California 95616, United States
- Department
of Nutrition, University of California, Davis, Davis, California 95616, United States
- West
Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, California 95616, United States
| | - Alan R. Brash
- Department
of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Mats Hamberg
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Larodan
Research Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - Craig E. Wheelock
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Department
of Respiratory Medicine and Allergy, Karolinska
University Hospital, Stockholm SE-141-86, Sweden
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28
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Zhang Z, Zhang C. Regulation of cGAS-STING signalling and its diversity of cellular outcomes. Nat Rev Immunol 2025:10.1038/s41577-024-01112-7. [PMID: 39774812 DOI: 10.1038/s41577-024-01112-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 01/11/2025]
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway, which recognizes both pathogen DNA and host-derived DNA, has emerged as a crucial component of the innate immune system, having important roles in antimicrobial defence, inflammatory disease, ageing, autoimmunity and cancer. Recent work suggests that the regulation of cGAS-STING signalling is complex and sophisticated. In this Review, we describe recent insights from structural studies that have helped to elucidate the molecular mechanisms of the cGAS-STING signalling cascade and we discuss how the cGAS-STING pathway is regulated by both activating and inhibitory factors. Furthermore, we summarize the newly emerging understanding of crosstalk between cGAS-STING signalling and other signalling pathways and provide examples to highlight the wide variety of cellular processes in which cGAS-STING signalling is involved, including autophagy, metabolism, ageing, inflammation and tumorigenesis.
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Affiliation(s)
- Zhengyin Zhang
- School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China
| | - Conggang Zhang
- School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
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Guo F, Zhang J, Gao Y, Shu Z, Sun F, Ma J, Zhou X, Li W, Mao H, Lei X. Discovery and Total Synthesis of Anhydrotuberosin as a STING Antagonist for Treating Autoimmune Diseases. Angew Chem Int Ed Engl 2025; 64:e202407641. [PMID: 39471366 DOI: 10.1002/anie.202407641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/22/2024] [Accepted: 10/24/2024] [Indexed: 11/01/2024]
Abstract
Excessive activation of the stimulator of the interferon gene (STING) pathway has been identified as a significant contributor to various autoimmune diseases, such as STING-associated vasculopathy with infantile-onset (SAVI) and inflammatory bowel disease (IBD). However, discovering effective STING antagonists for treating STING-mediated autoimmune disorders remains challenging. Herein, we identified the natural product anhydrotuberosin (ATS) as a potent STING antagonist by a high-throughput chemical screen and follow-up biological validations. However, the limited supply from natural product isolation impeded the pharmacological evaluations of ATS. Accordingly, we developed a concise and scalable total synthesis of ATS in 6 steps. Enabled by total synthesis, we further extensively investigated ATS's mode of action and evaluated its therapeutic potential. Remarkably, ATS inhibits STING signaling in PBMCs derived from three SAVI patients. ATS showed decent pharmacokinetic parameters and strongly alleviated tissue inflammation in DSS-induced IBD colitis and Trex1-/- autoimmune animal models with low toxicity. Collectively, this research lays the foundation for developing novel STING antagonists as an effective therapy for autoinflammatory and autoimmune diseases.
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Affiliation(s)
- Fusheng Guo
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
- Peking-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Jing Zhang
- Jiangsu JITRI Molecular Engineering Inst. Co., Ltd., Jiangsu, 215500, China
| | - Yihui Gao
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
| | - Zhou Shu
- Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory for Genetics of Birth Defects, Beijing, 100045, China
| | - Fei Sun
- Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory for Genetics of Birth Defects, Beijing, 100045, China
| | - Jing Ma
- Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory for Genetics of Birth Defects, Beijing, 100045, China
| | - Xu Zhou
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
- Peking-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Wenyang Li
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
| | - Huawei Mao
- Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory for Genetics of Birth Defects, Beijing, 100045, China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
- Peking-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
- Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China
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30
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Zhang X, He B, Lu J, Bao Q, Wang J, Yang Y. The crucial roles and research advances of cGAS‑STING pathway in liver diseases. Ann Med 2024; 56:2394588. [PMID: 39183465 PMCID: PMC11348815 DOI: 10.1080/07853890.2024.2394588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/17/2024] [Accepted: 08/01/2024] [Indexed: 08/27/2024] Open
Abstract
Inflammation responses have identified as a key mediator of in various liver diseases with high morbidity and mortality. cGAS-STING signalling is essential in innate immunity since it triggers release of type I interferons and various of proinflammatory cytokines. The potential connection between cGAS-STING pathway and liver inflammatory diseases has recently been reported widely. In our review, the impact of cGAS-STING on liver inflammation and regulatory mechanism are summarized. Furthermore, many inhibitors of cGAS-STING signalling as promising agents to cure liver inflammation are also explored in detail. A comprehensive knowledge of molecular mechanisms of cGAS-STING signalling in liver inflammation is vital for exploring novel treatments and providing recommendations and perspectives for future utilization.
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Affiliation(s)
- Xiaoqian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiongling Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yida Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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31
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Zhang YJ, Chen LY, Lin F, Zhang X, Xiang HF, Rao Q. ROS responsive nanozyme loaded with STING silencing for the treatment of sepsis-induced acute lung injury. Toxicol Appl Pharmacol 2024; 493:117155. [PMID: 39537108 DOI: 10.1016/j.taap.2024.117155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Acute lung injury (ALI) is a common complication of sepsis and a leading cause of mortality in septic patients. Studies indicate that STING may play a crucial role in the pathogenesis of sepsis-induced ALI by interacting with the PARP-1/NLRP3 pathway. Therefore, targeting STING inhibition has potential as a novel therapeutic strategy for ALI. However, effective inhibition remains challenging due to the widespread expression of STING across various tissues. In this study, we developed a nanozyme-based drug delivery system, DSPE-TK-mPEG-MnO2@siSTING (abbreviated as DTmM@siSTING), using DSPE-TK-mPEG-MnO2 as the carrier, and characterized it via scanning electron microscopy, dynamic light scattering, nanoparticle size analysis, and gel electrophoresis. To evaluate the therapeutic effects of DTmM@siSTING, an in vitro ALI cell model and an in vivo ALI mouse model were established, assessing the nanozyme's impact on ROS levels, inflammatory responses, and the PARP-1/NLRP3 pathway in sepsis-induced ALI. Results demonstrated that DTmM@siSTING exhibited good physiological stability. In vitro, DTmM@siSTING significantly reduced ROS levels, myeloperoxidase activity, and expression of inflammatory cytokines, while also inhibiting PARP-1/NLRP3 pathway activation. In vivo experiments further revealed that DTmM@siSTING effectively delivered siSTING to the lungs, mitigating sepsis-induced ALI and associated inflammatory responses. Additionally, DTmM@siSTING displayed excellent biocompatibility. In summary, our findings suggest that DTmM@siSTING significantly enhances the therapeutic efficacy of siSTING, alleviating ALI by inhibiting ROS production, inflammatory responses, and activation of the PARP-1/NLRP3 pathway. This novel approach presents a promising therapeutic avenue for sepsis-induced ALI.
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Affiliation(s)
- Yin-Jin Zhang
- Blood Purification Center, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China
| | - Ling-Yang Chen
- Blood Purification Center, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China
| | - Feng Lin
- Department of Anesthesiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China
| | - Xia Zhang
- Department of Anesthesiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China
| | - Hai-Fei Xiang
- Department of Anesthesiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China.
| | - Qing Rao
- Department of Anesthesiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China.
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32
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Soh LJ, Lee SY, Roebuck MM, Wong PF. Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy. Life Sci 2024; 357:123112. [PMID: 39378929 DOI: 10.1016/j.lfs.2024.123112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 09/20/2024] [Accepted: 10/03/2024] [Indexed: 10/10/2024]
Abstract
Osteoarthritis (OA) is a debilitating chronic degenerative disease affecting the whole joint organ leading to pain and disability. Cellular stress and injuries trigger inflammation and the onset of pathophysiological changes ensue after irreparable damage and inability to resolve inflammation, impeding the completion of the healing process. Extracellular matrix (ECM) degradation leads to dysregulated joint tissue metabolism. The reparative effort induces the proliferation of hypertrophic chondrocytes and matrix protein synthesis. Aberrant protein synthesis leads to endoplasmic reticulum (ER) stress and chondrocyte apoptosis with consequent cartilage matrix loss. These events in a vicious cycle perpetuate inflammation, hindering the restoration of normal tissue homeostasis. Recent evidence suggests that inflammatory responses and chondrocyte apoptosis could be caused by the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling axis in response to DNA damage. It has been reported that there is a crosstalk between ER stress and cGAS-STING signalling in cellular senescence and other diseases. Based on recent evidence, this review discusses the role of ER stress, Unfolded Protein Response (UPR) and cGAS-STING pathway in mediating inflammatory responses in OA.
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Affiliation(s)
- Li-Jen Soh
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Siam-Yee Lee
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Margaret M Roebuck
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK; Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L3 9TA, UK
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
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Elshoura Y, Herz M, Gad MZ, Hanafi R. Nitro fatty acids: A comprehensive review on analytical methods and levels in health and disease. Anal Biochem 2024; 694:115624. [PMID: 39029643 DOI: 10.1016/j.ab.2024.115624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 07/07/2024] [Accepted: 07/17/2024] [Indexed: 07/21/2024]
Abstract
Nitro fatty acids (NO2-FAs) are biologically active compounds produced from the reaction of unsaturated fatty acids with reactive nitrogen species (RNS). Due to their electrophilic nature, these endogenously produced metabolites can react with nucleophilic targets, producing a spectrum of modulatory and protective effects. Determination of NO2-FAs in biological samples is challenging due to their low nanomolar to picomolar endogenous concentrations, indistinct metabolism, and distribution in many tissues and biofluids. Several attempts have been made to develop precise, standardized, and efficient methodologies for assessing physiological and pathophysiological processes to overcome the difficulties associated with their measurement. This review discusses those approaches utilizing liquid chromatography tandem mass spectrometry (LC‒MS/MS) and gas chromatography tandem mass spectrometry (GC‒MS/MS) for the quantification of NO2-FAs, in addition to a summary of their laboratory synthesis and extraction from biological samples. Clinical associations with different pathological conditions, including hyperlipidaemia, cardiac ischemia and herpes simplex type 2 viral infection (HSV-2), are also discussed.
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Affiliation(s)
- Yasmin Elshoura
- Department of Pharmaceutical Chemistry, German University in Cairo, Egypt
| | - Magy Herz
- Department of Pharmaceutical Chemistry, German University in Cairo, Egypt.
| | - Mohamed Z Gad
- Department of Biochemistry, German University in Cairo, Egypt
| | - Rasha Hanafi
- Department of Pharmaceutical Chemistry, German University in Cairo, Egypt
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34
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Yu L, Liu P. cGAS/STING signalling pathway in senescence and oncogenesis. Semin Cancer Biol 2024; 106-107:87-102. [PMID: 39222763 PMCID: PMC11625615 DOI: 10.1016/j.semcancer.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 08/25/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
The cGAS/STING signaling pathway is a crucial component of the innate immune system, playing significant roles in sensing cytosolic DNA, regulating cellular senescence, and contributing to oncogenesis. Recent advances have shed new lights into the molecular mechanisms governing pathway activation in multiple pathophysiological settings, the indispensable roles of cGAS/STING signaling in cellular senescence, and its context-dependent roles in cancer development and suppression. This review summarizes current knowledge related to the biology of cGAS/STING signaling pathway and its participations into senescence and oncogenesis. We further explore the clinical implications and therapeutic potential for cGAS/STING targeted therapies, and faced challenges in the field. With a focus on molecular mechanisms and emerging pharmacological targets, this review underscores the importance of future studies to harness the therapeutic potential of the cGAS/STING pathway in treating senescence-related disorders and cancer. Advanced understanding of the regulatory mechanisms of cGAS/STING signaling, along with the associated deregulations in diseases, combined with the development of new classes of cGAS/STING modulators, hold great promises for creating novel and effective therapeutic strategies. These advancements could address current treatment challenges and unlock the full potential of cGAS/STING in treating senescence-related disorders and oncogenesis.
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Affiliation(s)
- Le Yu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Pengda Liu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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35
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Tian M, Li F, Pei H, Liu X, Nie H. The role of the cGAS-STING pathway in chronic pulmonary inflammatory diseases. Front Med (Lausanne) 2024; 11:1436091. [PMID: 39540037 PMCID: PMC11557406 DOI: 10.3389/fmed.2024.1436091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 09/06/2024] [Indexed: 11/16/2024] Open
Abstract
The innate immune system plays a vital role in the inflammatory process, serving as a crucial mechanism for the body to respond to infection, cellular stress, and tissue damage. The cGAS-STING signaling pathway is pivotal in the onset and progression of various autoimmune diseases and chronic inflammation. By recognizing cytoplasmic DNA, this pathway initiates and regulates inflammation and antiviral responses within the innate immune system. Consequently, the regulation of the cGAS-STING pathway has become a prominent area of interest in the treatment of many diseases. Chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis, are characterized by persistent or recurrent lung inflammation and tissue damage, leading to diminished respiratory function. This paper explores the mechanism of action of the cGAS-STING signaling pathway in these diseases, examines the development of STING inhibitors and nanomaterial applications, and discusses the potential clinical application prospects of targeting the cGAS-STING pathway in chronic inflammatory lung diseases.
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Affiliation(s)
- Mengxiang Tian
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Fengyuan Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Haiping Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoling Liu
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongyun Nie
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing, China
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36
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Fan MW, Tian JL, Chen T, Zhang C, Liu XR, Zhao ZJ, Zhang SH, Chen Y. Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications. World J Diabetes 2024; 15:2041-2057. [PMID: 39493568 PMCID: PMC11525733 DOI: 10.4239/wjd.v15.i10.2041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 08/14/2024] [Accepted: 08/26/2024] [Indexed: 09/26/2024] Open
Abstract
Diabetes mellitus (DM) is one of the major causes of mortality worldwide, with inflammation being an important factor in its onset and development. This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway in mediating inflammatory responses. Furthermore, it comprehensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM, diabetic gastroenteropathy, diabetic cardiomyopathy, non-alcoholic fatty liver disease, and other complications. Additionally, the role of cGAS-STING in autonomic dysfunction and intestinal dysregulation, which can lead to digestive complications, has been discussed. Altogether, this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.
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Affiliation(s)
- Ming-Wei Fan
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Jin-Lan Tian
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Tan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Can Zhang
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Xin-Ru Liu
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Zi-Jian Zhao
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Shu-Hui Zhang
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Yan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
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Li R, Liu H, Liu Y. The cGAS-STING pathway and female reproductive system diseases. Front Immunol 2024; 15:1447719. [PMID: 39445027 PMCID: PMC11496054 DOI: 10.3389/fimmu.2024.1447719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/17/2024] [Indexed: 10/25/2024] Open
Abstract
The cGAS-STING pathway has become a crucial role in the detection of cytosolic DNA and the initiation of immune responses. The cGAS-STING pathway not only mediates protective immune defense against various DNA-containing pathogens but also detects tumor-derived DNA to generate intrinsic anti-tumor immunity. However, abnormal activation of the cGAS-STING pathway by self-DNA can also lead to autoimmune diseases and inflammatory disorders. This article reviews the mechanisms and functions of the cGAS-STING pathway, as well as the latest research progress in female reproductive-related diseases. We focus on the regulatory mechanisms and roles of this pathway in common female reproductive disorders, discuss the clinical potential of the cGAS-STING pathway as biomarkers and therapeutic agents for female reproductive diseases, as well as the research controversies, technical issues, and biological knowledge gaps that need to be resolved. Furthermore, we provide new ideas for the treatment and prevention of these diseases.
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Affiliation(s)
- Ruijie Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hengwei Liu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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38
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Wang MM, Zhao Y, Liu J, Fan RR, Tang YQ, Guo ZY, Li T. The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases. Acta Pharmacol Sin 2024; 45:1997-2010. [PMID: 38822084 PMCID: PMC11420349 DOI: 10.1038/s41401-023-01185-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/18/2023] [Indexed: 06/02/2024]
Abstract
Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.
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Affiliation(s)
- Ming-Ming Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, 999078, China
| | - Yue Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, 999078, China
| | - Juan Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, 999078, China
| | - Rong-Rong Fan
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, 14183, Sweden
| | - Yan-Qing Tang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, 999078, China
| | - Zheng-Yang Guo
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, 999078, China
| | - Ting Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, 999078, China.
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39
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Zhu Q, Zhou H. The role of cGAS-STING signaling in rheumatoid arthritis: from pathogenesis to therapeutic targets. Front Immunol 2024; 15:1466023. [PMID: 39386207 PMCID: PMC11461283 DOI: 10.3389/fimmu.2024.1466023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily characterized by erosive and symmetric polyarthritis. As a pivotal axis in the regulation of type I interferon (IFN-I) and innate immunity, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has been implicated in the pathogenesis of RA. This pathway mainly functions by regulating cell survival, pyroptosis, migration, and invasion. Therefore, understanding the sources of cell-free DNA and the mechanisms underlying the activation and regulation of cGAS-STING signaling in RA offers a promising avenue for targeted therapies. Early detection and interventions targeting the cGAS-STING signaling are important for reducing the medical burden on individuals and healthcare systems. Herein, we review the existing literature pertaining to the role of cGAS-STING signaling in RA, and discuss current applications and future directions for targeting the cGAS-STING signaling in RA treatments.
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Affiliation(s)
- Qiugang Zhu
- Department of Laboratory Medicine, Shangyu People’s Hospital of Shaoxing, Shaoxing University, Shaoxing, China
| | - Huimin Zhou
- Department of Laboratory Medicine, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi, China
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Pei S, Piao HL. Exploring Protein S-Palmitoylation: Mechanisms, Detection, and Strategies for Inhibitor Discovery. ACS Chem Biol 2024; 19:1868-1882. [PMID: 39160165 DOI: 10.1021/acschembio.4c00110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2024]
Abstract
S-palmitoylation is a reversible and dynamic process that involves the addition of long-chain fatty acids to proteins. This protein modification regulates various aspects of protein function, including subcellular localization, stability, conformation, and biomolecular interactions. The zinc finger DHHC (ZDHHC) domain-containing protein family is the main group of enzymes responsible for catalyzing protein S-palmitoylation, and 23 members have been identified in mammalian cells. Many proteins that undergo S-palmitoylation have been linked to disease pathogenesis and progression, suggesting that the development of effective inhibitors is a promising therapeutic strategy. Reducing the protein S-palmitoylation level can target either the PATs directly or their substrates. However, there are rare clinically effective S-palmitoylation inhibitors. This review aims to provide an overview of the S-palmitoylation field, including the catalytic mechanism of ZDHHC, S-palmitoylation detection methods, and the functional impact of protein S-palmitoylation. Additionally, this review focuses on current strategies for expanding the chemical toolbox to develop novel and effective inhibitors that can reduce the level of S-palmitoylation of the target protein.
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Affiliation(s)
- Shaojun Pei
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023, Dalian, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Hai-Long Piao
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023, Dalian, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, 110122 Shenyang, China
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41
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Zhang SD, Li H, Zhou YL, Liu XC, Li DC, Hao CF, You QD, Xu XL. Protein-protein interactions in cGAS-STING pathway: a medicinal chemistry perspective. Future Med Chem 2024; 16:1801-1820. [PMID: 39263789 PMCID: PMC11457635 DOI: 10.1080/17568919.2024.2383164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 07/09/2024] [Indexed: 09/13/2024] Open
Abstract
Protein-protein interactions (PPIs) play pivotal roles in biological processes and are closely linked with human diseases. Research on small molecule inhibitors targeting PPIs provides valuable insights and guidance for novel drug development. The cGAS-STING pathway plays a crucial role in regulating human innate immunity and is implicated in various pathological conditions. Therefore, modulators of the cGAS-STING pathway have garnered extensive attention. Given that this pathway involves multiple PPIs, modulating PPIs associated with the cGAS-STING pathway has emerged as a promising strategy for modulating this pathway. In this review, we summarize an overview of recent advancements in medicinal chemistry insights into cGAS-STING PPI-based modulators and propose alternative strategies for further drug discovery based on the cGAS-STING pathway.
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Affiliation(s)
- Shi-Duo Zhang
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hui Li
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ye-Ling Zhou
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xue-Chun Liu
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - De-Chang Li
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Chuan-Feng Hao
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qi-Dong You
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiao-Li Xu
- State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
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42
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Li X, Yu T, Li X, He X, Zhang B, Yang Y. Role of novel protein acylation modifications in immunity and its related diseases. Immunology 2024; 173:53-75. [PMID: 38866391 DOI: 10.1111/imm.13822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 05/21/2024] [Indexed: 06/14/2024] Open
Abstract
The cross-regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in cutting-edge fields such as metabolic regulatory mechanisms in immune cell development and function, and metabolic targets and immune-related disease pathways. Protein post-translational modification (PTM) is a key epigenetic mechanism that regulates various biological processes and highlights metabolite functions. Currently, more than 400 PTM types have been identified to affect the functions of several proteins. Among these, metabolic PTMs, particularly various newly identified histone or non-histone acylation modifications, can effectively regulate various functions, processes and diseases of the immune system, as well as immune-related diseases. Thus, drugs aimed at targeted acylation modification can have substantial therapeutic potential in regulating immunity, indicating a new direction for further clinical translational research. This review summarises the characteristics and functions of seven novel lysine acylation modifications, including succinylation, S-palmitoylation, lactylation, crotonylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation and malonylation, and their association with immunity, thereby providing valuable references for the diagnosis and treatment of immune disorders associated with new acylation modifications.
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Affiliation(s)
- Xiaoqian Li
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, People's Republic of China
| | - Tao Yu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xiaolu Li
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xiangqin He
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, People's Republic of China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, People's Republic of China
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43
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Li Y, Zhao D, Chen D, Sun Q. Targeting protein condensation in cGAS-STING signaling pathway. Bioessays 2024; 46:e2400091. [PMID: 38962845 DOI: 10.1002/bies.202400091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 07/05/2024]
Abstract
The cGAS-STING signaling pathway plays a pivotal role in sensing cytosolic DNA and initiating innate immune responses against various threats, with disruptions in this pathway being associated with numerous immune-related disorders. Therefore, precise regulation of the cGAS-STING signaling is crucial to ensure appropriate immune responses. Recent research, including ours, underscores the importance of protein condensation in driving the activation and maintenance of innate immune signaling within the cGAS-STING pathway. Consequently, targeting condensation processes in this pathway presents a promising approach for modulating the cGAS-STING signaling and potentially managing associated disorders. In this review, we provide an overview of recent studies elucidating the role and regulatory mechanism of protein condensation in the cGAS-STING signaling pathway while emphasizing its pathological implications. Additionally, we explore the potential of understanding and manipulating condensation dynamics to develop novel strategies for mitigating cGAS-STING-related disorders in the future.
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Affiliation(s)
- Yajie Li
- Institute of Biomedical Research, Yunnan University, Kunming, China
| | - Dongbo Zhao
- Institute of Biomedical Research, Yunnan University, Kunming, China
| | - Dahua Chen
- Institute of Biomedical Research, Yunnan University, Kunming, China
- Southwest United Graduate School, Kunming, China
| | - Qinmiao Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Key Laboratory of Organ Regeneration and Reconstruction, Beijing, China
- School of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
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Fryer AL, Abdullah A, Mobilio F, Jobling A, Moore Z, de Veer M, Zheng G, Wong BX, Taylor JM, Crack PJ. Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury. Br J Pharmacol 2024; 181:3118-3135. [PMID: 38710660 DOI: 10.1111/bph.16347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 01/04/2024] [Accepted: 01/16/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND AND PURPOSE Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. EXPERIMENTAL APPROACH This study investigated the neuroprotective effects of the small-molecule STING inhibitor n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post-TBI. KEY RESULTS Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines Tnf-α, Il-1β and Cxcl10 compared to their vehicle-treated counterparts 2 h post-TBI. CONCLUSION AND IMPLICATIONS This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma-induced inflammation and neuroprotective potential.
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Affiliation(s)
- Amelia L Fryer
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
| | - Amar Abdullah
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Subang Jaya, Malaysia
| | - Frank Mobilio
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
| | - Andrew Jobling
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Australia
| | - Zachery Moore
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Michael de Veer
- Monash Biomedical Imaging, Monash University, Clayton, Australia
| | - Gang Zheng
- Monash Biomedical Imaging, Monash University, Clayton, Australia
| | - Bruce X Wong
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
| | - Juliet M Taylor
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
| | - Peter J Crack
- Neuropharmacology Laboratory, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
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45
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Zheng ZH, Wang JJ, Lin JG, Ye WL, Zou JM, Liang LY, Yang PL, Qiu WL, Li YY, Yang SJ, Zhao M, Zhou Q, Li CZ, Li M, Li ZM, Zhang DM, Liu PQ, Liu ZP. Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol. Acta Pharmacol Sin 2024; 45:1879-1897. [PMID: 38689095 PMCID: PMC11336235 DOI: 10.1038/s41401-024-01281-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/28/2024] [Indexed: 05/02/2024]
Abstract
Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.
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Affiliation(s)
- Zhi-Hua Zheng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
- National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jiao-Jiao Wang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Jiu-Guo Lin
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Wei-le Ye
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Jia-Mi Zou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Li-Yin Liang
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ping-Lian Yang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Wan-Lu Qiu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, 510006, China
| | - Yuan-Yuan Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Si-Jia Yang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Man Zhao
- School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China
| | - Qing Zhou
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, 510006, China
| | - Cheng-Zhi Li
- Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510006, China
| | - Min Li
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
- National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Zhuo-Ming Li
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Dong-Mei Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Pei-Qing Liu
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
- National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
| | - Zhi-Ping Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China.
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
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Kozu KT, Nascimento RRNRD, Aires PP, Cordeiro RA, Moura TCLD, Sztajnbok FR, Pereira IA, Almeida de Jesus A, Perazzio SF. Inflammatory turmoil within: an exploration of autoinflammatory disease genetic underpinnings, clinical presentations, and therapeutic approaches. Adv Rheumatol 2024; 64:62. [PMID: 39175060 DOI: 10.1186/s42358-024-00404-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 08/11/2024] [Indexed: 08/24/2024] Open
Abstract
Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1β release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, β, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFβ anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still's disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.
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Affiliation(s)
- Kátia Tomie Kozu
- Universidade de Sao Paulo, Faculdade de Medicina (USP FM), Sao Paulo, Brazil
| | | | - Patrícia Pontes Aires
- Universidade Federal de Sao Paulo, Escola Paulista de Medicina (Unifesp EPM), Rua Otonis, 863, Vila Clementino, São Paulo, SP, 04025-002, Brazil
| | | | | | - Flavio Roberto Sztajnbok
- Federal University of Rio de Janeiro: Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Sandro Félix Perazzio
- Universidade de Sao Paulo, Faculdade de Medicina (USP FM), Sao Paulo, Brazil.
- Universidade Federal de Sao Paulo, Escola Paulista de Medicina (Unifesp EPM), Rua Otonis, 863, Vila Clementino, São Paulo, SP, 04025-002, Brazil.
- Division of Immunology and Rheumatology, Fleury Laboratories, Sao Paulo, SP, Brazil.
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47
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Chang F, Gunderstofte C, Colussi N, Pitts M, Salvatore SR, Thielke AL, Turell L, Alvarez B, Goldbach-Mansky R, Villacorta L, Holm CK, Schopfer FJ, Hansen AL. Development of nitroalkene-based inhibitors to target STING-dependent inflammation. Redox Biol 2024; 74:103202. [PMID: 38865901 PMCID: PMC11215336 DOI: 10.1016/j.redox.2024.103202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/18/2024] [Accepted: 05/19/2024] [Indexed: 06/14/2024] Open
Abstract
Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.
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Affiliation(s)
- Fei Chang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | | | - Nicole Colussi
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Mareena Pitts
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA
| | - Sonia R Salvatore
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Anne L Thielke
- Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark
| | - Lucia Turell
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay
| | - Beatriz Alvarez
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay
| | - Raphaela Goldbach-Mansky
- Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20850, USA
| | - Luis Villacorta
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
| | - Christian K Holm
- Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark.
| | - Francisco J Schopfer
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Pittsburgh Heart, Lung, Blood, And Vascular Medicine Institute (VMI), Pittsburgh, PA, USA; Pittsburgh Liver Research Center (PLRC), Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine (C3M), Pittsburgh, PA, USA.
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48
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Chang L. Harnessing cGAS-STING axis for therapeutic benefits in systemic lupus erythematosus. Int J Rheum Dis 2024; 27:e15256. [PMID: 38982864 DOI: 10.1111/1756-185x.15256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 06/17/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024]
Abstract
The cyclic GMP-AMP synthase (cGAS), a prominent intracellular DNA sensor in mammalian cells, controls the innate immune response and the stimulator of interferon genes (STING)-mediated synthesis of pro-inflammatory cytokines, such as type-I interferon (IFN-I). For decades, IFN-I has been hypothesized to be essential in the development of systemic lupus erythematosus (SLE), a chronic multisystem autoimmunity characterized by immune complex (IC) deposition in small vessels. Recent findings revealed that the activation of the cGAS-STING pathway by self-DNA would propagate the autoimmune responses via upregulating IFN-I production in SLE. In this review, we aimed to provide a comprehensive outlook of the role of the cGAS-STING pathway in SLE pathobiology, as well as, a better understanding of current therapeutic opportunities targeting this axis.
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Affiliation(s)
- Liu Chang
- Department of Rheumatology, Henan Provincial Hospital of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
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49
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Yu X, Cai L, Yao J, Li C, Wang X. Agonists and Inhibitors of the cGAS-STING Pathway. Molecules 2024; 29:3121. [PMID: 38999073 PMCID: PMC11243509 DOI: 10.3390/molecules29133121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/14/2024] Open
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Several agonists and inhibitors of the cGAS-STING pathway have been developed and evaluated for the treatment of various diseases. The agonists aim to activate STING, with cyclic dinucleotides (CDNs) being the most common, while the inhibitors aim to block the enzymatic activity or DNA binding ability of cGAS. Meanwhile, non-CDN compounds and cGAS agonists are also gaining attention. The omnipresence of the cGAS-STING pathway in vivo indicates that its overactivation could lead to undesired inflammatory responses and autoimmune diseases, which underscores the necessity of developing both agonists and inhibitors of the cGAS-STING pathway. This review describes the molecular traits and roles of the cGAS-STING pathway and summarizes the development of cGAS-STING agonists and inhibitors. The information is supposed to be conducive to the design of novel drugs for targeting the cGAS-STING pathway.
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Affiliation(s)
- Xiaoxuan Yu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Linxiang Cai
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Jingyue Yao
- Department of Pharmacy, Fourth Military Medical University, Xi’an 710032, China;
| | - Cenming Li
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaoyong Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
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Xu Q, Xing J, Wang S, Peng H, Liu Y. The role of the cGAS-STING pathway in metabolic diseases. Heliyon 2024; 10:e33093. [PMID: 38988528 PMCID: PMC11234105 DOI: 10.1016/j.heliyon.2024.e33093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 07/12/2024] Open
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical innate immune pathway primarily due to its vital DNA sensing mechanism in pathogen defence. Recent research advances have shown that excessive activation or damage to the cGAS-STING pathway can exacerbate chronic inflammatory responses, playing a significant role in metabolic dysfunction and aging, leading to the development of related diseases such as obesity, osteoporosis, and neurodegenerative diseases. This article reviews the structure and biological functions of the cGAS-STING signaling pathway and discusses in detail how this pathway regulates the occurrence and development of metabolic and age-related diseases. Additionally, this article introduces potential small molecule drugs targeting cGAS and STING, aiming to provide new research perspectives for studying the pathogenesis and treatment of metabolic-related diseases.
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Affiliation(s)
- Qian Xu
- Department of Endocrinology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Medical School of Nanjing Medical University, Zhenjiang, 212002, China
| | - Jie Xing
- Department of Laboratory Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Medical School of Nanjing Medical University, Zhenjiang, 212002, China
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Medical School of Nanjing Medical University, Zhenjiang, 212002, China
| | - Huiyong Peng
- Department of Laboratory Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Medical School of Nanjing Medical University, Zhenjiang, 212002, China
| | - Yingzhao Liu
- Department of Endocrinology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Medical School of Nanjing Medical University, Zhenjiang, 212002, China
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