IMMUNITY
·
2025
·
IF 26.3
Jing Han,Shuhao Zhang,Yanfei Hou,Yi Wang,Zhengyin Zhang,Jiaming Yang,Yifang Xu,Zexu Peng,Hang Yin,Kehong Chen,Xiangyu Liu,Conggang Zhang
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.
研究领域:
免疫学
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结构生物学
·
细胞信号传导
·
天然免疫
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Shaofeng Wang,Quanwei Li,Pan Guo,Luna Su,Tingyu Liang,Wenlan Yu,Qingwen Yang,Jianying Guo,Zhaoxin Tang,Jianzhao Liao
Terbuthylazine (TBA) is a widely employed pesticide that has been found to be a significant source of food and environmental pollution. Excessive exposure to TBA raises considerable apprehension regarding its potential impact on biological health, but its underlying toxic mechanisms have not been reported. Our findings indicated that TBA exposure could cause intestinal damage , as evidenced by decrease in the quantity of cupped cells and decrease in the expression of intestinal barrier-related proteins (Claudin-1, Occludin , ZO-1, and JAM-1). Additionally, exposure to TBA resulted in a significant decrease in the expression levels of oxidative stress-related genes and proteins. Furthermore, the expression of 8-hydroxy-2′-deoxyguanosine was significantly upregulated. Additionally, excessive exposure to TBA led to a substantial release of mitochondrial DNA, which further activated the cGAS-STING pathway and caused TBK1 and IRF3 phosphorylation. Meanwhile, mitophagy was activated under TBA exposure, as evidenced by decrease in the protein and gene levels of p62 and increase in the levels of PINK1 , PARKIN and LC3 II. Therefore, our results suggested that TBA exposure induced oxidative stress in the jejunum and caused mtDNA leakage, for activating the cGAS-STING pathway, which in turn promoted mitophagy . These findings revealed the toxicity mechanisms of TBA, which provided new insights into food safety caused by pesticide contamination.
研究领域:
毒理学
·
分子生物学
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产品关联
DOI
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-11
·
IF 5.2
Qin Danhui,Song Hui,Wang Caiwei,Ma Xiaojie,Fu Yu,Zhao Chunyuan,Zhao Wei,Zhang Lei,Zhang Weifang
Stimulator of interferon genes (STING) is vital in the cytosolic DNA-sensing process and critical for initiating the innate immune response, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases. Zinc finger CCCH-type antiviral protein 1 (ZC3HAV1) specifically binds the CpG dinucleotides in the viral RNAs of multiple viruses and promotes their degradation. ZAPS (ZC3HAV1 short isoform) is a potent stimulator of retinoid acid-inducible gene I (RIG-I) signaling during the antiviral response. However, how ZC3HAV1 controls STING signaling is unclear. Here, we show that ZC3HAV1 specifically potentiates STING activation by associating with STING to promote its oligomerization and translocation from the endoplasmic reticulum (ER) to the Golgi, which facilitates activation of IRF3 and NF-κB pathway. Accordingly, Zc3hav1 deficiency protects mice against herpes simplex virus-1 (HSV-1) infection- or 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced inflammation in a STING-dependent manner. These results indicate that ZC3HAV1 is a key regulator of STING signaling, which suggests its possible use as a therapeutic target for STING-dependent inflammation.
研究领域:
免疫学
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病毒学
·
炎症性疾病
✓ 已验证
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Yue Chen,Di Wu,Quan Li,Zhenghua Wei,Qian Liu,Jin Li,Daohui Gong,Chaowang Huang,Qianyi You,Hang Qian,Guansong Wang
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause severe lung inflammation and damage, compromising respiratory function. Nanomedicine offers hope in controlling this inflammation. DNA nanostructures, as drug carriers, stand out due to their non-toxic, programmable, and precisely controllable traits. However, they face challenges in physiological stability and functionalization as carriers. Here, we introduce TET AG , DNA tetrahedra assembled and functionalized with aminoguanidine without magnesium. Aminoguanidine not only aids tetrahedron assembly but also inhibits the cyclic GMP-AMP synthase and stimulator of interferon (cGAS-STING) pathway, a key inflammatory signal. By integrating STING siRNA into TET AG (TET AG -STING), we achieve synergistic anti-inflammatory effects in ALI/ARDS. Our results show that TET AG offers improved stability and cellular uptake. Importantly, TET AG -STING exhibits potent anti-inflammatory activity in vitro and in a Lipopolysaccharides-induced mouse model following intratracheal administration. This significantly improves lung injury scores and pulmonary functions. These findings underscore aminoguanidine’s therapeutic potential in ALI/ARDS and highlight the promise of DNA nanostructures in medical applications.
研究领域:
医学
·
纳米医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2024
·Vol. 212
·期 7
·1188-1195
·
IF 3.6
Li Qizhao,Jia Mutian,Song Hui,Peng Jun,Zhao Wei,Zhang Weifang
STING-mediated DNA sensing pathway plays a crucial role in the innate antiviral immune responses. Clarifying its regulatory mechanism and searching STING agonists has potential clinical implications. Although multiple STING agonists have been developed to target cancer, there are few for the treatment of infectious diseases. Astaxanthin, a natural and powerful antioxidant, serves many biological functions and as a potential candidate drug for many diseases. However, how astaxanthin combats viruses and whether astaxanthin regulates the cyclic GMP-AMP synthase–STING pathway remains unclear. In this study, we showed that astaxanthin markedly inhibited HSV-1–induced lipid peroxidation and inflammatory responses and enhanced the induction of type I IFN in C57BL/6J mice and mouse primary peritoneal macrophages. Mechanistically, astaxanthin inhibited HSV-1 infection and oxidative stress-induced STING carbonylation and consequently promoted STING translocation to the Golgi apparatus and oligomerization, which activated STING-dependent host defenses. Thus, our study reveals that astaxanthin displays a strong antiviral activity by targeting STING, suggesting that astaxanthin might be a promising STING agonist and a therapeutic target for viral infectious diseases.
研究领域:
免疫学
·
病毒学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Shuang Liang,Haiyan Ma,Yue Liu,Linna Hai,Yiwei Tian,Yangyang Sun,Zhaohui Wang
The initiation of tumor-specific T cell responses is critically dependent on antigen-presenting cells (APCs). Nevertheless, as the most dominant APCs in tumors, M2-like macrophages largely restrained T cell activation due to inefficient antigen cross-presentation. Herein, we rationally designed a nano-immunomodulator (FANP) to restore the antigen presentation capability of M2-like macrophages by amplifying stimulator of interferon genes (STING) activation. FANPs were fabricated by self-assembly of Fe 3+ and Raddeanin A (RA), which rapidly degraded when reaching tumor microenvironment. The released Fe 3+ induced the polarization of M2-like macrophages into M1 phenotype, followed by RA stimulation for amplified STING activation, allowing robust antigen cross-presentation and T cell-driven anti-tumor response, leading to effective tumor regression in both immunogenic and poor-immunogenic tumor models. Notably, FANPs exhibited intensive STING activation in human tumor samples, showing potential for clinical impact. Our work offers a simple and robust strategy to re-educate M2-like macrophages by augmenting STING activation for cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2025
·
IF 4.6
Hongqiao Wei,Yongxin Chen,Zhenmin Qin,Honglei Wang,Yujia Liu,Tang Song,Yong Wu,Wanxiang Hu,Xiaowei Huang,Guodong Lu,Jing Zhou
Artesunate, a derivative of artemisinin, has a variety of pharmacological effects. Its potential application in ischemic brain injury still largely unknown. This study investigated the therapeutic effect and pharmacological mechanism of artesunate in neuronal injury following cerebral ischemia, and explore the potential role of lysosomal function and cGAS-STING signaling pathway in ischemia injury and artesunate treatment. Studies in rat models have revealed that artesunate can ameliorate neuronal injury and improve learning and memory function following ischemic insults. Furthermore, both in vivo and in vitro studies have confirmed that artesunate can protect neural cells from ischemic injury-induced cell death. Mechanistically, artesunate appears to exert its neuroprotective actions by activating lysosomal function and inhibiting the cGAS-STING pathway-mediated imflammatory repsonse. Our findings provide valuable insights into the therapeutic effects of artesunate exerting a neuroprotective role in chronic ischemic brain injury by activating lysosomal function, inhibiting the cGAS-STING pathway, and regulating the inflammatory response. This study offers a potential therapeutic strategy by regulating lysosome for the treatment of stroke and related neurological disorders.
研究领域:
神经科学
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药理学
·
炎症研究
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 3
·e70090
·
IF 4.2
Cailan Wang,Xinyi Lin,Shichun Guan,Qiaoyuan Wu,Shixiong Liang
Dihydroartemisinin (DHA) is a derivative of artemisinin, which affects inflammation, oxidative stress, and immune regulation. However, the mechanism underlying its effects remains largely unknown. This study aims to explore the mechanism by which DHA affects radiation-induced lung injury (RILI), providing new insights for lung radiotherapy. To elucidate its mechanism of action, C57BL/6 J mice were irradiated with 15 Gy whole chest. RILI was evaluated by qRT-PCR, ELISA, histology, Western blot analysis, immunohistochemistry, and RILI signaling cascade studies. In addition, small interfering RNAs were employed to knockdown cGAS proteins in the cGAS-STING signaling pathway in the human bronchial epithelium cell line (BEAS-2B). Both In Vivo and Vitro experiments were conducted to investigate the specific mechanism by which DHA alleviated RILI. We observed the activation of the cGAS-STING pathway, along with the phosphorylation of the downstream target NF-κB and an increase in inflammatory factor levels in the mouse model following radiation exposure. In the cell model, irradiation also triggered the activation of the cGAS-STING signaling pathway and its downstream targets, leading to elevated levels of inflammatory factors. Notably, knocking down the cGAS using small interfering RNA in the BEAS-2B cells significantly alleviated RILI in the cell model. Our study elucidated the mechanism of DHA reducing RILI through the cGAS/STING/NF-κB signaling pathway, and revealed that the GAS/STING/NF-κB axis may be a potential therapeutic target for RILI.
研究领域:
医学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Yuanxing Zhi,Jin Liu,Peihua Kuang,Xin Zhang,Ziwei Xu,Yanshan Chen,Xiuling Lin,Xiaoyan Wu,Pingzheng Zhou,Jianjun Chen
The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA and catalyzes the formation of 2′3′-cyclic-GMP-AMP (cGAMP), which in turn triggers interferon (IFN) production. Inappropriate activation of cGAS and production of cGAMP have been linked to a diversity of autoimmune diseases. The volume-regulated anion channels (VRACs) have been recently demonstrated to permeate cGAMP, thus making the channel essential for the activation of the cGAS-cGAMP-STING axis. DCPIB, a prominent inhibitor of VRAC channel, has been recently reported to also significantly activate TREK1 channel. Herein, in this study, we have designed and synthesized a series of novel DCPIB derivatives and investigated their potential regulatory effects on VRAC/TREK1 channels. Our results manifested that compound 6u was a dual inhibitor of VRAC/TREK1 channels with IC 50 s of 7.11 ± 0.94 μM and 4.43 ± 0.90 μM, respectively. On top of that, our data demonstrated that 6u impaired interferon production in a concentration-dependently manner by dampening cGAS-cGAMP-STING pathway without any cytotoxicity when it comes to herpes simplex virus type 1 (HSV1) infection. To sum up, our study not only discovered a novel DCPIB analog with dual inhibitory effects on VRAC/TREK1 channels but also provided a new strategy for the design and development of newly potent VRAC inhibitors, which benefits the treatment of cGAS-STING related autoimmune and inflammatory diseases .
研究领域:
药理学
·
免疫学
·
分子生物学
·
化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Stem Cell
·
2025
·
IF 20.4
Zemin Song,Yali Cui,Lilan Xin,Ruijing Xiao,Jingjing Feng,Conghui Li,Zhinang Yin,Honghong Wang,Qiuzi Li,Mengxuan Wang,Baoyi Lin,Yiming Zhang,Ying Zhou,Li Huang,Yanli He,Xiaoqing Li,Xiaoyan Liu,Shangqin Liu,Fuling Zhou,Zheng Liu,Hai-Bing Zhou,Pingping Fang,Kaiwei Liang
Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20 − PDH + mtDNA + mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.
研究领域:
细胞生物学
·
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 13
·e70688
·
IF 4.2
Li‐Ping Kang,Cong Xu,Pan Xu,Dong‐Hui Huang,Ze‐Bo Jiang
Non‐small cell lung cancer (NSCLC) stands as a predominant cause of cancer‐related mortality worldwide. Brazilin, an active isoflavonoid compound derived from Chinese herbs, has displayed anti‐cancer properties across various cancer cell lines. However, the precise anti‐tumour mechanism of Brazilin in NSCLC remains incompletely understood. In this paper, we demonstrated that Brazilin treatment significantly reduced the proliferation of NSCLC cells and induced apoptosis. Additionally, Brazilin caused G2 cell cycle arrest in NSCLC cells, characterised by decreased expression of Cyclin B1 and increased expression of P21. Brazilin also induced mitochondrial dysfunction and ROS production in NSCLC cells. Mechanistically, Brazilin treatment significantly activated the STING pathway and upregulated the expression of CXCL10, CXCL9, and CCL5 in NSCLC cell lines. Notably, the inhibition of the STING pathway with H‐151 enhances cell viability, suggesting STING is involved in Brazilin‐induced apoptosis. These findings underscore Brazilin as a promising anti‐cancer agent for NSCLC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Hua Chai,Renpeng Xia,Nan Ouyang,Jingyu Yao,Jiukun Hu,Minxuan Sun,Peng Miao
Reactive oxygen species (ROS) mediated cell damage is one of the most popular and effective ways for cancer therapy. However, overexpressed antioxidant of reduced glutathione (GSH) is always activated in tumor cells, which maintains redox equilibrium. Attempts to deplete GSH and elevate ROS levels can be potent therapeutic strategies. Herein, tumor cell membrane-encapsulated Fe 3 O 4 @MnO and 2′,3′-cyclic GMP-AMP (cGAMP) are prepared as the nanocatalyst for cancer therapy. The ionized Fe 3+ /Fe 2+ redox couple is utilized to initiate the Fenton reaction. Intracellular GSH level can thus be efficaciously controlled, and peroxide oxidation is catalyzed to produce excessive ROS. Meanwhile, cGAMP is released to trigger the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling axis. This targeted activation enhances the recruitment of macrophages, stimulates the secretion of critical pro-inflammatory cytokines, and consequently bolsters the efficacy of innate immune responses within the tumor microenvironment.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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