Acta Pharmacologica Sinica最新文献

{"title":"SOCS1 depletion drives osteosarcoma stemness and chemoresistance by suppressing ACTN4 degradation.","authors":"Jin-Yan Feng, Xian-Fu Wei, Long Chen, Hou-Zhi Yang, Yi-Qin Li, Jin-Wu Wang, Yong-Heng Liu, Yao Xu, Qing-Qian Zhao, Pu Li, Xiao-Dong Zhang, Guo-Wen Wang, Xiu-Xin Han","doi":"10.1038/s41401-025-01650-3","DOIUrl":"10.1038/s41401-025-01650-3","url":null,"abstract":"<p><p>Chemoresistance is a major factor contributing to the poor prognosis of osteosarcoma. Increasing evidence underscores the pivotal role of enhanced tumor stemness in driving drug resistance. In this study we investigated the molecular mechanisms underlying the chemoresistance and stemness in osteosarcoma. Two cisplatin-resistant osteosarcoma cell line models (U2OS-DDPr and 143B-DDPr) were established by culturing parental U2OS and 143B cells with escalating cisplatin concentrations (250 ng/mL to 2.5 µg/mL) over a 6-month period. We found that the expression levels of suppressor of cytokine signaling 1 (SOCS1), an E3 ubiquitin ligase, were markedly downregulated in both chemo-resistant osteosarcoma cells and osteosarcoma tumor specimens, and the reduced expression in tumor specimens was correlated to poor prognosis in osteosarcoma patients. Silencing SOCS1 significantly reduced cisplatin sensitivity, enhanced spheroid formation capacity, and upregulated the expression of stem cell markers including SOX2, OCT4, and CD44. Conversely, restoring SOCS1 expression reversed these effects both in vitro and in vivo. Immunoprecipitation-mass spectrometry analysis revealed that SOCS1 bound to ACTN4 and suppressed its protein expression by promoting K63-linked ubiquitination, ultimately leading to proteasomal degradation. Specifically, the SH2 domain of SOCS1 interacted with the N-terminal region of ACTN4, with Lys66 of ACTN4 playing a critical role in facilitating this interaction and subsequent ubiquitination. In addition, the expression of ACTN4 was highly enriched in chemo-resistant tissues, and its overexpression was positively associated with advanced tumor staging. Importantly, ACTN4 functioned as an oncogene to promote cisplatin resistance and stemness in osteosarcoma. Furthermore, we found that wortmannin, an inhibitor of ACTN4, could markedly block the effect of SOCS1 silencing on osteosarcoma aggressiveness. In conclusion, SOCS1 deletion promotes stemness and chemoresistance in osteosarcoma by inhibiting ACTN4 ubiquitination and degradation, which offers promising therapeutic targets for potentiating chemosensitivity in osteosarcoma.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938296","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}

{"title":"Ginsenoside Rh2 in combination with IFNγ potentiated the anti-cancer effect by enhancing interferon signaling response in colorectal cancer cells.","authors":"Mu-Yang Huang, Chun-Cao Xu, Qian Chen, Yan-Ming Zhang, Wen-Yu Lyu, Zi-Han Ye, Ting Li, Ming-Qing Huang, Jin-Jian Lu","doi":"10.1038/s41401-025-01557-z","DOIUrl":"10.1038/s41401-025-01557-z","url":null,"abstract":"<p><p>Interferon gamma (IFNγ) can amplify immune cell-mediated anti-tumor immunity, as well as directly kill cancer cells. Ginsenoside Rh2 (Rh2), a bioactive compound in traditional Chinese medicine, exhibits anti-cancer effects such as inhibiting proliferation and metastasis. Our earlier research found that Rh2 combined with IFNγ enhanced CXCL10 secretion in cancer cells. Here, we explored whether Rh2 and IFNγ exerted more potent anti-cancer activity in vitro and in vivo, along with its mechanisms and clinical value. Our data showed that Rh2 in combination with IFNγ resulted in a remarkably increased cytotoxicity in colorectal cancer cells including HT29, LoVo and T84 cell lines. Consistently, intratumoral injection with Rh2 plus IFNγ further restricted the HT29 tumor growth in vivo, and importantly, it was demonstrated to be safe for mice. Meanwhile, the combo treatment activated the stimulator of interferon genes (STING) pathway in cancer cells, promoting the transcription of downstream type I interferon. RNA sequencing revealed a dramatically transcriptional alteration in cancer cells with combo treatment and indicated that Rh2 further augmented the activation of interferon signaling pathway, compared with the IFNγ alone. Inhibition of janus kinase (JAK) by ruxolitinib could significantly rescue the cell death-triggered by the combo treatment. Then, a gene set named Rh2+IFNγ signature genes (RISG) was defined, which contained top 20 significantly upregulated genes from the combo treatment. Patients who exhibited a favorable response to the immunotherapy had a higher expression of RISG in tumor compared with those who did not respond. And the high expression of RISG was correlated with better clinical outcome in patients with colorectal cancer (CRC) and skin cutaneous melanoma (SKCM). Herein, the combination of Rh2 with IFNγ served as a promising strategy for cancer treatment, and its-derived RISG gene set also exhibited potential value in predicting clinical outcome. Schematic diagram of the anti-cancer effect of Rh2 combined with IFNγ. The schematic diagram illustrated that ginsenoside Rh2 in combination with IFNγ robustly activated the interferon signals in cancer cells, ultimately leading a significant cell death of cancer cells. ISGs, interferon-stimulated genes. Created with BioRender.com.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2534-2546"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"10.1038/s41401-025-01539-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2547-2563"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373879/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"10.1038/s41401-025-01547-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2407-2422"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374001/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-arrestin2: an emerging player and potential therapeutic target in inflammatory immune diseases.","authors":"Ping-Ping Gao, Ling Li, Ting-Ting Chen, Nan Li, Meng-Qi Li, Hui-Juan Zhang, Ya-Ning Chen, Shi-Hao Zhang, Wei Wei, Wu-Yi Sun","doi":"10.1038/s41401-024-01390-w","DOIUrl":"10.1038/s41401-024-01390-w","url":null,"abstract":"<p><p>β-arrestin2, a pivotal protein within the arrestin family, is localized in the cytoplasm, plasma membrane and nucleus, and regulates G protein-coupled receptors (GPCRs) signaling. Recent evidence shows that β-arrestin2 plays a dual role in regulating GPCRs by mediating desensitization and internalization, and by acting as a scaffold for the internalization, kinase activation, and the modulation of various signaling pathways, including NF-κB, MAPK, and TGF-β pathways of non-GPCRs. Earlier studies have identified that β-arrestin2 is essential in regulating immune cell infiltration, inflammatory factor release, and inflammatory cell proliferation. Evidently, β-arrestin2 is integral to the pathological mechanisms of inflammatory immune diseases, such as inflammatory bowel disease, sepsis, asthma, rheumatoid arthritis, organ fibrosis, and tumors. Research on the modulation of β-arrestin2 offers a promising strategy for the development of pharmaceuticals targeting inflammatory immune diseases. This review meticulously describes the roles of β-arrestin2 in cells associated with inflammatory immune responses and explores its pathological relevance in various inflammatory immune diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2347-2362"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alginate oligosaccharide prevents renal ischemia-reperfusion injury in rats via MRC1-mediated pathway.","authors":"Bai-En Liang, Luo-Sha Long, Xin-Yan Wu, Mei-Ying Huang, Ying Lai, Xi Yuan, Ming-Hui Wang, Meng Li, Qi-Qi Zheng, Hai-Ling Zhang, Man-Chun Chen, Zhen-de Liu, Xin Geng, Qian-Qian Lyu, Wei-Dong Wang, Qing-Hua Liu, Wei-Zhi Liu, Chun-Ling Li","doi":"10.1038/s41401-025-01545-3","DOIUrl":"10.1038/s41401-025-01545-3","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a clinical syndrome that is defined as a sudden decline in renal function and characterized by inflammation and tubular injury. Alginate oligosaccharide (AOSC), a natural product obtained from alginate by acidolysis and hydrolysis, shows activities of antioxidant, immunomodulation, and anti-inflammation. In this study, we investigated the potential of AOSC in the treatment of AKI. Renal ischemia-reperfusion (I/R) was induced in male rats by clipping both the renal artery and vein for 45 min followed by reperfusion for 24 h. The rats were treated with AOSC (100 mg/kg, i.g.) before surgery. At the end of the experiments, both kidneys were collected for protein, mRNA measurement, or histological analysis. We showed that AOSC pretreatment significantly improved glomerular and tubular function in the kidney of I/R rats. AOSC markedly inhibited I/R-induced activation of TLR4/MyD88/NF-κB/IL-1β inflammatory signaling and prevented apoptosis in the kidney. In HK2 cells subjected to hypoxia/reoxygenation (H/R) stimulation, AOSC (250-1000 μg/ml) dose-dependently prevented pro-inflammatory responses and cell apoptosis. Transcriptomic analysis revealed that I/R increased the expression levels of mannose receptor type C1 (MRC1) in the kidney, which was markedly inhibited by AOSC. Molecular docking showed that AOSC interacted with E725, N727, E733, T743, S745, and N747 of MRC1 through hydrogen bonds. MRC1 gene knockout significantly improved renal function and attenuated I/R-induced kidney inflammation and apoptosis in mice. In line with this, AOSC failed to prevent I/R-induced kidney injury in MRC1 gene knockout mice. UPLC analysis showed that the protection of AOSC in HK2 cells subjected to H/R was likely attributed to MRC1-mediated intracellular endocytosis. In conclusion, AOSC prevents I/R-induced AKI, which is at least partially mediated by MRC1.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2450-2467"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple and efficient method for purification of human pluripotent stem cell-derived cardiomyocytes via activating p53.","authors":"Peng Zhang, Sen-le Rao, Xiao-Chen Wang, Ping Liang, Ji-Zhen Lu, Wen-Wen Jia, Huang-Tian Yang","doi":"10.1038/s41401-025-01543-5","DOIUrl":"10.1038/s41401-025-01543-5","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2583-2585"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PDE4 inhibitor apremilast ameliorates TNBS-induced irritable bowel syndrome in mice by activating the Nrf-2 signaling pathway in enteric glial cells.","authors":"Yu-Hao Lu, Shu-Yue Lei, Tao Yang, You-Sheng Xu, Hong-Lin Wang, Chun-Lan Feng, Wei Tang","doi":"10.1038/s41401-025-01649-w","DOIUrl":"10.1038/s41401-025-01649-w","url":null,"abstract":"<p><p>Enteric glial cells (EGCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP). Increased PDE4 activity promotes excessive production of pro-inflammatory cytokines and chemokines in various immune and epithelial cells, exacerbating immune cell activation and infiltration in inflamed tissues, inhibition of PDE4 has been proven to be an important strategy for inflammatory and autoimmune diseases. In this study we investigated the pathological role of PDE4 and the therapeutic effects of a PDE4 inhibitor apremilast in IBS. 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced IBS model was established in mice, the mice were treated with apremilast (50 mg/kg, i.g.) for 7 days. After treatment, the intestinal motility and visceral sensitivity were assessed. At the end of the study, the mice were euthanized and the blood and colon tissues were collected for analyses. We showed that apremilast treatment significantly ameliorated IBS symptoms in the mice, evidenced by improvement on delayed intestinal motility and visceral hypersensitivity. We found that EGCs were activated in the colon of IBS mice. We then demonstrated that apremilast (10 μM) significantly suppressed TNF-α/IFN-γ stimulated activation of rat EGC cell line CRL-2690 and primary EGCs in vitro, as well as the secretion of EGCs-derived pain mediators and inflammatory factors while ameliorating oxidative stress. These effects depended on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway, which was validated in Nrf-2 knockout EGCs. These results suggest that inhibition of PDE4 by apremilast suppresses EGCs activation by activating the Nrf-2 signaling pathway, leading to decreased expression of pain mediators and inflammatory factors while ameliorating oxidative stress, ultimately alleviating IBS.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938344","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}

{"title":"The PIWI-interacting RNA CRAPIR alleviates myocardial ischemia‒reperfusion injury by reducing p53-mediated apoptosis via binding to SRSF1.","authors":"Hong Yan, Han Li, Dao-Hong Yin, Zi-Zhen Zhang, Qian-Yun Zhang, Zhong-Yu Ren, Yu Hu, Gui-Yang Zheng, Yu Liu, Wen-Ya Ma, Yi-Ning Liu, Xiu-Xiu Wang, Ben-Zhi Cai, Hong-Yang Chen","doi":"10.1038/s41401-025-01534-6","DOIUrl":"10.1038/s41401-025-01534-6","url":null,"abstract":"<p><p>Ischemia-reperfusion (I/R) injury refers to the secondary damage that occurs when blood flow is restored to heart tissues and organs following a period of prolonged ischemia. This damage is exacerbated primarily through mechanisms such as oxidative stress, inflammatory responses and apoptosis, all of which can severely impact patient prognosis. PIWI-interacting RNAs (piRNAs) represent a novel class of small noncoding RNAs that play pivotal roles in regulating gene expression and cellular functions. However, the precise role and underlying mechanisms of piRNAs in I/R injury remain poorly understood. In this study, we investigated the role and molecular mechanisms of a cardiac regeneration-associated PIWI-interacting RNA (CRAPIR), previously identified by our team, in I/R injury. An I/R injury model was established in adult male mice. The protein levels of cleaved caspase-3, Bax, Bcl2 and p53 were assessed using Western blotting, and cardiomyocyte apoptosis was detected via TUNEL staining. Our study revealed that, in I/R-damaged heart tissues and hypoxia‒reoxygenation (H/R)-induced cardiomyocyte models, CRAPIR was upregulated 24 h after I/R and H/R but was markedly downregulated at 72 h after I/R injury and 48 h after H/R injury. In the I/R mouse model, agomir-mediated overexpression of CRAPIR alleviated heart dysfunction and reduced cardiomyocyte apoptosis caused by I/R injury. Conversely, CRAPIR knockdown via an antagomir exacerbated I/R-induced cardiac dysfunction and increased the number of apoptotic cardiomyocytes. Mechanistically, CRAPIR interacts with serine/arginine-rich splicing factor 1 (SRSF1), triggering the upregulation of murine double minute 2 (MDM2) expression. The increased MDM2 promoted p53 ubiquitination, leading to reduced p53 levels. Furthermore, silencing SRSF1 or MDM2 attenuated the protective effect of CRAPIR against cardiomyocyte apoptosis following H/R injury. These findings suggest that CRAPIR serves as a critical regulator of I/R injury via the SRSF1/MDM2/p53 signaling pathway.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2393-2406"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"10.1038/s41401-025-01540-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2376-2392"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373991/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}