Acta Pharmacologica Sinica最新文献_第6页

Immune cells in systemic lupus erythematosus: biology and traditional Chinese medicine therapy. 系统性红斑狼疮的免疫细胞：生物学和中医治疗。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-17 DOI: 10.1038/s41401-025-01554-2

Ya-Nan Liang, Luo Chen, Qing-Yu Huang, Yu-Ting Song, Yu-Juan Fan, Tong-Qing Chen, Jia-Hui Ni, Dong Wang, Xiao-Yan Shen, Yi-Ming Wang, Yan You

引用次数: 0

NSCLC cells sustain phase separation of cytoplasmic membrane-less organelles to protect themselves against cisplatin treatment. 非小细胞肺癌细胞维持细胞质无膜细胞器的相分离以保护自己免受顺铂治疗。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-17 DOI: 10.1038/s41401-025-01551-5

Ning-Ning Li, Ling-Ling Rao, Dan Su, Bin-Hao Liu, Guo-Qiang Ma, Hong-Feng Wang, Zeng-Li Zhang, Zheng Ying

{"title":"NSCLC cells sustain phase separation of cytoplasmic membrane-less organelles to protect themselves against cisplatin treatment.","authors":"Ning-Ning Li, Ling-Ling Rao, Dan Su, Bin-Hao Liu, Guo-Qiang Ma, Hong-Feng Wang, Zeng-Li Zhang, Zheng Ying","doi":"10.1038/s41401-025-01551-5","DOIUrl":"https://doi.org/10.1038/s41401-025-01551-5","url":null,"abstract":"Cisplatin is the first platinum compound used for anticancer therapy, including non-small cell lung cancer (NSCLC). However, the clinical efficacy of cisplatin is strongly limited by cisplatin resistance. Hence, illuminating the mechanism of cisplatin resistance will aid in the development of therapeutic strategies that improve the sensitivity of cancer cells to cisplatin. Interestingly, membrane-less organelles, which are formed through biomolecular condensation in association with phase separation, have been recently linked with cancers. Here, we reveal a new molecular basis of cisplatin resistance in NSCLC, showing that cisplatin kills cancer cells by the alteration of cytoplasmic membrane-less organelles. Specifically, cisplatin treatment results in the disassembly of processing bodies (PBs) and the assembly of stress granule (SG)-like granules which are different from canonical SGs in NSCLC cells, but not cisplatin-resistant NSCLC cells. Moreover, alterations of PBs and noncanonical SG-like granules are associated with cisplatin-induced cancer cell death. Importantly, we found that disrupting PBs and canonical SGs with cycloheximide and FDA-approved pyrvinium helps cisplatin to kill cisplatin-resistant NSCLC cells. Taken together, our findings provide insight into the role of membrane-less organelle regulation in cisplatin resistance and offer an effective solution for overcoming cisplatin resistance in NSCLC.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Complexin 2 contributes to the protective effect of NAD⁺ on neuronal survival following neonatal hypoxia-ischemia. 复合素2参与NAD+对新生儿缺氧缺血后神经元存活的保护作用。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-17 DOI: 10.1038/s41401-025-01555-1

Xiao-Wen Xu, Xiu-Wen Zhou, Li Zhang, Qing Wang, Xin-Xin Wang, Yi-Ming Jin, Li-Li Li, Mei-Fang Jin, Hai-Ying Wu, Xin Ding, Hong Ni

{"title":"Complexin 2 contributes to the protective effect of NAD+ on neuronal survival following neonatal hypoxia-ischemia.","authors":"Xiao-Wen Xu, Xiu-Wen Zhou, Li Zhang, Qing Wang, Xin-Xin Wang, Yi-Ming Jin, Li-Li Li, Mei-Fang Jin, Hai-Ying Wu, Xin Ding, Hong Ni","doi":"10.1038/s41401-025-01555-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01555-1","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in cell metabolism associated with aging, cancer, neurodegenerative diseases and metabolic disorders. We recently showed that NAD+ therapy significantly improved neurobehavioral outcomes in neonatal mice after hypoxia-ischemia (HI), and bioinformatics analysis revealed that the expression of complexin 2 (CPLX2) in the injured cerebral cortex was significantly decreased 24 h after HI injury but could be reversed by NAD+ intervention. In this study we explored the role of CPLX2 in the survival and function of neonatal hypoxic-ischemic cortical neurons. HI models were established by permanent ligation of the left common carotid artery in mice. CPLX2-knockdown lentiviral vector was injected intraventricularly on postnatal day 1 (P1); CPLX2 knockout mice were also used. NAD+ (5 mg·kg-1·d-1, i.p.) was administered before HI surgery, thereafter once a day until sampling. We showed that NAD+ administration significantly ameliorated the morphological damages and neurobehavioral defects, and elevated the seizure thresholds in HI mice. All the beneficial effects of NAD+ were abolished by CPLX2 knockdown or knockout. In HT22 neuronal cells subjected to OGD/R, pretreated with NAD+ (100 μM) for 12 h significantly increased the cell viability, decreased the LDH levels, and inhibited the ferroptosis evidenced by the changes in redox-related parameters including concentrations of Fe2+, GSH, MDA, H2O2 as well as the expression of GPX4 and SLC7A11. CPLX2 knockdown in HT22 neuronal cells blocked the protective effects of NAD+ as in HI mice, whereas CPLX2 overexpression enhanced the inhibitory effects of NAD+ on ferroptosis in HT22 neuronal cells.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice. 孕烷X受体通过激活yes相关蛋白减轻脓毒症诱导的小鼠肝损伤。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-15 DOI: 10.1038/s41401-025-01552-4

Cheng-Hua Wu, Shuang Hu, Dan Li, Xiao-Wen Jiang, Hui Ou-Yang, Guo-Fang Bi, Peng Wang, Feng-Ting Liang, Wen-Hong Zhou, Xiao Yang, Jian-Hong Fang, Hui-Chang Bi

{"title":"Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice.","authors":"Cheng-Hua Wu, Shuang Hu, Dan Li, Xiao-Wen Jiang, Hui Ou-Yang, Guo-Fang Bi, Peng Wang, Feng-Ting Liang, Wen-Hong Zhou, Xiao Yang, Jian-Hong Fang, Hui-Chang Bi","doi":"10.1038/s41401-025-01552-4","DOIUrl":"https://doi.org/10.1038/s41401-025-01552-4","url":null,"abstract":"The severity of sepsis is attributed to excessive inflammatory responses leading to liver injury. Pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, has been implicated in regulating inflammation and liver regeneration. This study aimed to investigate the role of PXR in sepsis-induced liver injury and the underlying mechanisms. Sepsis models were established in mice, the mice were administered the typical mouse PXR agonist PCN (100 mg·kg-1·d-1, i.p.) for 3 consecutive days in advance, then subjected to CLP operation or LPS administration 1 h after the last administration of PCN. The results showed that PCN pretreatment significantly increased the survival rate of septic mice, while the survival rate was reduced after the knockout of Pxr. In addition, PCN pretreatment effectively alleviated sepsis-induced liver injury. In Pxr knockout mice, liver injury was more severe, whereas the protective effects of PCN pretreatment were abolished. Mechanistically, PCN pretreatment significantly upregulated the expression of yes-associated protein (YAP) and its downstream targets and decreased the level of phosphorylated nuclear factor-κB (NF-κB). Moreover, liver-specific knockdown of Yap blocked the protective effects of PCN pretreatment against sepsis-induced liver injury and downregulated the phosphorylation level of NF-κB. In summary, this study demonstrated that PXR activation protects against sepsis-induced liver injury through activation of the YAP signaling pathway, providing a new strategy for the diagnosis and treatment of sepsis-induced liver injury.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integration of machine learning and experimental validation reveals new lipid-lowering drug candidates. 机器学习和实验验证的整合揭示了新的降脂候选药物。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-15 DOI: 10.1038/s41401-025-01539-1

Jing-Hong Chen, Ke-Xin Li, Chao-Fan Fan, Hong Yang, Zhi-Rou Zhang, Yi-Han Chen, Chang Qi, Ang-Hua Li, An-Qi Lin, Xin Chen, Peng Luo

{"title":"Integration of machine learning and experimental validation reveals new lipid-lowering drug candidates.","authors":"Jing-Hong Chen, Ke-Xin Li, Chao-Fan Fan, Hong Yang, Zhi-Rou Zhang, Yi-Han Chen, Chang Qi, Ang-Hua Li, An-Qi Lin, Xin Chen, Peng Luo","doi":"10.1038/s41401-025-01539-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01539-1","url":null,"abstract":"Hyperlipidemia, a major risk factor for cardiovascular diseases, is associated with limitations in clinical lipid-lowering medications. Drug repurposing strategies expedite the research process and mitigate development costs, offering an innovative approach to drug discovery. This study employed systematic literature and guidelines review to compile a training set comprising 176 lipid-lowering drugs and 3254 non-lipid-lowering drugs. Multiple machine learning models were developed to predict the lipid-lowering potential of drugs. A multi-tiered validation strategy was implemented, encompassing large-scale retrospective clinical data analysis, standardized animal studies, molecular docking simulations and dynamics analyses. Through a comprehensive screening analysis utilizing machine learning, 29 FDA-approved drugs with lipid-lowering potential were identified. Clinical data analysis confirmed that four candidate drugs, with Argatroban as the representative, demonstrated lipid-lowering effects. In animal experiments, the candidate drugs significantly improved multiple blood lipid parameters. Molecular docking and dynamics simulations elucidated the binding patterns and stability of candidate drugs in interaction with related targets. We successfully identified multiple non-lipid-lowering drugs with lipid-lowering potential by integrating state-of-the-art machine learning techniques with multi-level validation methods, thereby providing new insights into lipid-lowering drugs, establishing a paradigm for AI-based drug repositioning research, and expanding the repertoire of lipid-lowering medications available to clinicians.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipin1-dependent transcriptional inactivation of SREBPs contributes to selinexor sensitivity in multiple myeloma. 脂素1依赖的SREBPs转录失活有助于多发性骨髓瘤中selinexor的敏感性。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-14 DOI: 10.1038/s41401-025-01553-3

Jun-Ying Wang, Meng-Ping Chen, Jin-Xing Jiang, Yi-Ke Wan, Xin Li, Yi-Wei Zhang, Yi Fang, Hong-Hui Huang, Zhao-Yu Qin, Jian Hou

{"title":"Lipin1-dependent transcriptional inactivation of SREBPs contributes to selinexor sensitivity in multiple myeloma.","authors":"Jun-Ying Wang, Meng-Ping Chen, Jin-Xing Jiang, Yi-Ke Wan, Xin Li, Yi-Wei Zhang, Yi Fang, Hong-Hui Huang, Zhao-Yu Qin, Jian Hou","doi":"10.1038/s41401-025-01553-3","DOIUrl":"https://doi.org/10.1038/s41401-025-01553-3","url":null,"abstract":"Selective nuclear export inhibitor selinexor (SEL) represents a promising therapeutic strategy for relapsed/refractory multiple myeloma (RRMM). But its mechanisms of action as well as factors that influence therapeutic responses have not been fully characterized yet. In this study we employed catTFRE proteomics technique to profile changes in nuclear abundance of activated transcription factors (TFs)/co-factors (TCs) in myeloma cells following SEL treatment. We found that pharmacological inhibition of exportin-1 (XPO1) by SEL leads to a significant nuclear accumulation of Lipin1 in NCI-H929 cells. Nuclear-localized Lipin1 acted as a transcriptional cofactor that suppressed the transcriptional activity of SREBPs. By performing subcellular localization analysis, molecular docking, co-immunoprecipitation and other assays, we demonstrated that Lipin1 was subjected to XPO1-dependent nuclear export. We demonstrated that SEL downregulated the expression of key lipogenesis-related genes regulated by SREBPs including FASN, SCD, DHCR24 and FDPS, leading to reduced fatty acid and cholesterol synthesis in MM cell lines and primary CD138+ cells. Using shRNA-mediated knockdown assays, we elucidated the critical role of Lipin1 in mediating the inhibitory effects of SEL on the SREBPs pathway and its contribution to SEL sensitivity both in vitro and in murine xenograft models. In conclusion, we reveal a novel mechanism by which SEL downregulates cellular lipid biosynthesis, thereby inhibiting the proliferation of myeloma cells. This study highlights the critical role of Lipin1 in the anti-myeloma effects of SEL, suggesting its potential as a biomarker for identifying patients who are most likely to benefit from SEL-based therapies.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

JOSD2 alleviates acute kidney injury through deubiquitinating SIRT7 and negativity regulating SIRT7-NF-κB inflammatory pathway in renal tubular epithelial cells. JOSD2通过去泛素化SIRT7和负性调节肾小管上皮细胞SIRT7- nf -κB炎症通路减轻急性肾损伤。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-11 DOI: 10.1038/s41401-025-01546-2

Ying Zhao, Qing-Qing Zhao, Shi-Jie Fan, Di-Yun Xu, Li-Ming Lin, Wu Luo, Bo-Zhi Ye, Chun-Peng Zou, Hong Zhu, Zai-Shou Zhuang, Yun-Jie Zhao, Guang Liang

{"title":"JOSD2 alleviates acute kidney injury through deubiquitinating SIRT7 and negativity regulating SIRT7-NF-κB inflammatory pathway in renal tubular epithelial cells.","authors":"Ying Zhao, Qing-Qing Zhao, Shi-Jie Fan, Di-Yun Xu, Li-Ming Lin, Wu Luo, Bo-Zhi Ye, Chun-Peng Zou, Hong Zhu, Zai-Shou Zhuang, Yun-Jie Zhao, Guang Liang","doi":"10.1038/s41401-025-01546-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01546-2","url":null,"abstract":"Acute kidney injury (AKI), triggered by various stimuli including ischemia-reperfusion, nephrotoxic insult, and sepsis, is characterized by an abrupt deterioration in kidney function. Ubiquitination is a post-translational modification of proteins that plays a critical role in the pathogenesis and progression of AKI. In this study, we aimed to investigate the role and underlying mechanism of the deubiquitinating enzyme Josephin Domain-containing protein 2 (JOSD2) in AKI. We found that deficiency of JOSD2 exacerbated renal tubular injury and inflammation in AKI mice induced by cisplatin or ischemia-reperfusion injury. Conversely, the specific overexpression of JOSD2 in renal tubular epithelial cells effectively prevented renal tubular injury and inflammation induced in AKI mice. Mechanistically, we identified Sirtuin 7 (SIRT7) as a potential substrate of JOSD2 through mass spectrometry combined with co-immunoprecipitation analysis. JOSD2 removes the K63-linked ubiquitination of SIRT7 via its active site C24 and promotes P62-mediated autophagic degradation of SIRT7, which subsequently prevents the phosphorylation and nuclear translocation of P65 and reduces inflammatory responses in renal tubular epithelial cells. Our study reveals the role of the JOSD2-SIRT7 axis in regulating AKI-induced renal inflammation and highlights the potential of JOSD2 as a promising therapeutic target for AKI.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice. 更正：不可逆ErbB家族阻滞剂阿法替尼治疗小鼠非小细胞肺癌脑内转移的疗效。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-09 DOI: 10.1038/s41401-025-01542-6

Shi-Rong Zhang, Lu-Cheng Zhu, Yan-Ping Jiang, Jing Zhang, Ru-Jun Xu, Ya-Si Xu, Bing Xia, Sheng-Lin Ma

引用次数: 0

Wogonin attenuates septic cardiomyopathy by suppressing ALOX15-mediated ferroptosis. Wogonin通过抑制alox15介导的铁下垂来减轻脓毒性心肌病。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-09 DOI: 10.1038/s41401-025-01547-1

Hua Ye, Lin Wu, Yan-Mei Liu, Jun-Xia Zhang, Huan-Tao Hu, Mao-Long Dong, Jun Ren

{"title":"Wogonin attenuates septic cardiomyopathy by suppressing ALOX15-mediated ferroptosis.","authors":"Hua Ye, Lin Wu, Yan-Mei Liu, Jun-Xia Zhang, Huan-Tao Hu, Mao-Long Dong, Jun Ren","doi":"10.1038/s41401-025-01547-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01547-1","url":null,"abstract":"Septic cardiomyopathy (SCM), a severe complication in sepsis, significantly increases the mortality of septic patients. Ferroptosis, an iron-regulated cell death, has been implicated in the development of SCM. Wogonin, a flavonoid from the root of the skullcap, exhibits anti-inflammatory, anti-allergic, and anti-apoptotic activities. In this study, we investigated the effects of wogonin on SCM and associated cardiomyocyte ferroptosis. Cecal ligation and puncture (CLP) surgery was performed in mice to establish a SCM model. Wogonin (20, 40 and 60 mg·kg-1, i.p.) was administered 2 h prior to CLP surgery. We showed that wogonin pretreatment dose-dependently mitigated CLP-induced cardiac dysfunction, myocardial damage, and deranged cardiomyocyte contractility. Furthermore, wogonin pretreatment ameliorated cardiac inflammation, oxidative stress, and mitochondrial dysfunction in CLP-challenged mice. We demonstrated that wogonin exerted the cardioprotective effects through suppressing cardiomyocyte ferroptosis both in vivo and in vitro. We revealed that wogonin directly bound to and inhibited ALOX15 (arachidonic acid 15-lipoxygenase), a lipoxygenase that governed the oxidation of polyunsaturated fatty acids to initiate ferroptosis. Pharmacological inhibition of ALOX15 using a specific inhibitor ML351 (10 mg·kg-1·d-1, i.p. for 7 days prior to CLP surgery) markedly diminished cardiac abnormalities and cardiomyocyte ferroptosis in CLP-challenged mice. In LPS-challenged HL-1 cardiomyocytes, overexpression of ALOX15 or supplement of its downstream metabolite 15-HpETE (1 μM) diminished the anti-ferroptotic effects of wogonin. Our results demonstrate that wogonin protects against SCM through inhibition of ALOX15-meditated ferroptosis.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage. 小胶质细胞STING激活促进实验性脑出血小鼠的神经炎症和病理改变。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-08 DOI: 10.1038/s41401-025-01540-8

Yu-Xiao Xue, Yi-Jun Chen, Mei-Zhen Qin, Fan-Fan Shang, Yi-Ting Lu, Yu-Hao Sun, Liu-Guan Bian, Ao Zhang, Yang Yu, Chun-Yong Ding

{"title":"Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage.","authors":"Yu-Xiao Xue, Yi-Jun Chen, Mei-Zhen Qin, Fan-Fan Shang, Yi-Ting Lu, Yu-Hao Sun, Liu-Guan Bian, Ao Zhang, Yang Yu, Chun-Yong Ding","doi":"10.1038/s41401-025-01540-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01540-8","url":null,"abstract":"Neuroinflammation, a significant contributor to secondary brain injury, plays a critical role in the pathological process and prognosis of intracerebral haemorrhage (ICH). Thus, developing interventions to mitigate secondary neuroimmune deterioration is of paramount importance. Currently, no effective immunomodulatory drugs are available for ICH. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a recently identified innate immune-sensing pathway primarily expressed in microglia within the central nervous system (CNS) that has been implicated in the pathophysiology of various neurological diseases. In this study we investigated the role of cGAS-STING pathway in ICH. A collagenase model of ICH was established in mice. Brain tissues were collected on D1 or D3 post-ICH. We observed a significant increase in double-stranded (dsDNA) levels and activation of the cGAS-STING pathway in the perihaematomal region of ICH mice. Administration of a blood brain barrier-permeable STING antagonist H151 (10 mg/kg, i.p.) significantly decreased cell apoptosis, alleviated hematoma growth, and improved motor impairments in ICH mice, accompanied by inhibiting the STING pathway in microglia, reducing production/release of the cGAS-STING pathway downstream inflammatory factors, NLRP3 inflammasome activation and gasdermin D (GSDMD)-induced microglial pyroptosis. Microglial Sting conditional knockout significantly mitigated ICH-induced neuroinflammatory responses, pathological damage and motor dysfunction. These results suggest that the microglial STING pathway promotes brain pathological damage and behavioural defects in ICH mice by activating the NLRP3 inflammasome and microglial pyroptosis. The STING pathway may serve as a potential therapeutic target for ICH-induced secondary brain injury.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0