Acta Pharmacologica Sinica最新文献

{"title":"FNDC5/Irisin exacerbates APAP-induced acute liver injury through activating JNK/NF-κB and inflammatory response.","authors":"Qian-Hui Zhang, Lei-Ming Jin, Meng-Sha Lin, Min-Xiu Wang, Ya-Qian Cui, Jia-Xi Ye, Yong-Qiang Xiong, Wu Luo, Wei-Wei Zhu, Guang Liang","doi":"10.1038/s41401-025-01509-7","DOIUrl":"10.1038/s41401-025-01509-7","url":null,"abstract":"<p><p>Acute liver injury (ALI) is associated with high mortality rates. Despite its severity, there are currently no effective interventions, underscoring the urgent need for research on the mechanisms driving ALI progression. Irisin, a hormone derived from its precursor FNDC5, has been shown to play a critical role in some chronic liver diseases. In this study we investigated the role of hepatic FNDC5/Irisin in a mouse model of AILI induced by acetaminophen (APAP, 400 mg/kg, i.p.). The mice were euthanized at 6, 12 and 24 h after APAP injection, then the blood and liver tissues were collected for analyses. By conducting transcriptome sequencing, we identified that both the expression and release of FNDC5/Irisin were significantly increased and highly correlated with AILI. We showed that knockout of Irisin significantly improved APAP-induced tissue damage and hepatocyte death in mouse liver. Conversely, preinjection of recombinant Irisin protein (1 mg·kg^-1·d^-¹, i.p., for 3 days) exacerbated the AILI in FNDC5 knockout mice. RNA-seq analysis revealed that knockout of FNDC5/Irisin reduced inflammatory responses and JNK/NF-κB activation in APAP-treated mouse liver, while exogenous Irisin administration aggravated JNK/NF-κB-mediated inflammation. In primary mouse hepatocytes treated with APAP (15 mM), application of Irisin (100 ng/mL) activated the integrin αV/JNK/NF-κB axis, driving inflammation and oxidative stress. In summary, this study highlights Irisin as a critical regulator in AILI progression. Circulating Irisin could be a novel biomarker for AILI diagnosis, and targeting FNDC5/Irisin could hold promise for the development of novel treatments for AILI.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1946-1957"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522398","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":"CYP2A6 suppresses hepatocellular carcinoma via inhibiting SRC/Wnt/β-Catenin pathway.","authors":"Yi-Fan Liu, Li-Ya Feng, Wan-Ying Zhang, Xu Zhang, Li-Jun Shao, Xiao-Man Zhao, Jian-Bo Ji, Xiu-Li Guo","doi":"10.1038/s41401-025-01524-8","DOIUrl":"10.1038/s41401-025-01524-8","url":null,"abstract":"<p><p>Patients with hepatocellular carcinoma (HCC) at advanced stages face limited treatment options, highlighting the urgent need for more effective early detection methods and advanced therapeutic modalities. Emerging evidence shows that multiple CYP450 proteins are involved in the pathogenesis of HCC. CYP1A2, CYP2E1 and CYP3A5 have been shown to modulate important signaling pathways, hereby inhibiting the proliferation and invasion of HCC cells. In this study we investigated the role of cytochrome P-450 2A6 (CYP2A6) in HCC progression, focusing on its potential as a diagnostic biomarker and therapeutic target. By analyzing TCGA and GEO databases, we found that the expression levels of CYP2A6 were significantly decreased in HCC compared to normal tissues. Overexpression of CYP2A6 resulted in reduced proliferation, migration, invasion, adhesion, tube-forming in PLC/PRF/5 and HepG2 cells in vitro, as well as tumorigenicity and metastasis in nude mice. Notably, the anti-HCC effects of CYP2A6 were independent of its metabolic functions. We demonstrated that CYP2A6 could bind to proto-oncogene tyrosine-protein kinase SRC (SRC) and inhibit the SRC/Wnt/β-Catenin pathway. Overexpression of SRC abrogated the inhibitory effects of upregulating CYP2A6 on the migration and invasion of PLC/PRF/5 cells. These results together suggest the potential of CYP2A6 as a biomarker and therapeutic target for HCC. Its modulation of the SRC/Wnt/β-Catenin pathway provides a new insight for HCC treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2029-2040"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603107","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":"LMO7 drives profibrotic fibroblast polarization and pulmonary fibrosis in mice through TGF-β signalling.","authors":"Lei Sun, Hai-Bo Zhang, Hong-Chao Jiang, Wen Li, Meng-Kai Li, Xin-Yi Yang, Yuan-Yuan Cai, Ke-Ke Xue, Yu-Sen Gou, Xin-Yue Liu, Qing Liang, Lu-Gen Zuo, Jian-Guo Hu, Feng Qian","doi":"10.1038/s41401-025-01488-9","DOIUrl":"10.1038/s41401-025-01488-9","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive lethal disease. Profibrotic fibroblast polarization during wound healing is one of the main causes of IPF, and the molecular mechanisms involved have yet to be fully determined. LIM domain-only protein 7 (LMO7), which acts as an E3 ubiquitin ligase, is highly expressed in the lung, brain and heart and plays important roles in embryonic development, cancer progression, inflammatory bowel disease and Dreifuss muscular dystrophy (EDMD). In this study, we investigated the role of LMO7 in pulmonary fibrosis. Bleomycin (BLM)-induced lung fibrosis was established in mice. For AAV-mediated gene therapy, AAV-Lmo7 shRNA (AAV-Lmo7 shRNA) was intratracheally administered 6 days before BLM injection. Through transcriptome analysis, we found that the expression of LMO7 was significantly upregulated in the fibroblasts of IPF patients and BLM-induced mice. Knockdown of LMO7 impaired the profibrotic phenotype of fibroblasts in BLM-treated mice and in primary lung fibroblasts stimulated with TGF-β in vitro. We observed that LMO7 binds to SMAD7, mediating its degradation by polyubiquitination of lysine 70 and increasing the stability of TGF-β receptor 1 (TGFβR1). Finally, intratracheal administration of adeno-associated virus (AAV)-mediated Lmo7 shRNA significantly ameliorated the progression of BLM-induced lung fibrosis. Our results suggest that LMO7 is a promising target for blocking profibrotic fibroblast polarization for the treatment of fibrotic lung disease. A model for the role of LMO7 in TGF-β/SMAD signaling during pulmonary fibrosis. During pulmonary fibrosis, ubiquitin E3 ligase LMO7 is up-regulated, and binds with. SMAD7. LMO7 mediates the ubiquitination of SMAD7 on Lysine 70, leading to its degradation, and further enhances the stability of transforming growth factor-beta receptor 1 (TGFβR1).</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1930-1945"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497801","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":"High-fat intake during lactation ameliorates cardiac fatty acid metabolic disorders and dysfunction in mouse offspring undergoing prenatal poly (I:C) stimulation.","authors":"Liang Song, Meng Meng, Yan Ji, Jian Peng, Xiao Guan, Yao Yang, Xiao-Feng Yin, Tao Liu, Kun-Peng Tian, Qing-Hua Bi, Jun-Ping Wang, Xiao-Hui Li, Yue Cai, You-Cai Deng","doi":"10.1038/s41401-025-01497-8","DOIUrl":"10.1038/s41401-025-01497-8","url":null,"abstract":"<p><p>Prenatal inflammation exposure (PIE) is associated with increased prevalence of cardiovascular diseases (CVDs) in offspring, including heart failure and hypertension. In this study, we investigated the molecular mechanisms underlying the prenatal programming of cardiac function. Pregnant mice were injected with poly (I:C) (20 mg/kg, i.p.) on day 10.5 of gestation. Mothers and pubs were fed with high-fat diet during lactation. Cardiac tissues of the offspring were collected for analysis. We found that prenatal poly (I:C) exposure significantly reduced fatty acid metabolism and impaired the homeostasis of energy metabolism in the heart tissues of offspring at the age of 4 weeks. RNA-sequencing analysis of the heart tissues revealed that prenatal poly (I:C) exposure resulted in decreased expression of the fatty acid oxidation-related enzymes and increased expression of glycolysis-related enzymes, enabling rewiring of energy metabolism. High-fat intake during lactation partially ameliorated cardiac fatty acid metabolism in the heart tissues and prevented cardiac dysfunction in offspring mice exposed to prenatal poly (I:C) at the age of 16 weeks. Collectively, abnormal cardiac fatty acid metabolism accounts for the prenatal poly (I:C) exposure-induced cardiac dysfunction, highlighting the potential of dietary interventions to prevent cardiac dysfunction for PIE offspring.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1920-1929"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497818","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":"Ginsenoside Rg1 alleviates chronic stress-induced depression in rats by targeting Cx43-YAP axis.","authors":"Hui-Qin Wang, Rui-Fang Zheng, Qi-di Ai, Song-Wei Yang, Xue-Ying Yang, Ai-Ping Chen, Qian Yan, Xu Yan, Zhao Zhang, Jian-Guo Xing, Shi-Feng Chu, Zhen-Zhen Wang, Yan-Tao Yang, Nai-Hong Chen","doi":"10.1038/s41401-025-01515-9","DOIUrl":"10.1038/s41401-025-01515-9","url":null,"abstract":"<p><p>Although significant progress has been made in the development of antidepressants, a large subpopulation of individuals remains unresponsive to existing treatments. Ginsenoside Rg1 (Rg1), a natural compound with well-defined antidepressant effects and low-cost administrations, holds therapeutic promise but requires mechanistic elucidation for clinical translation. Based on our previous finding that Rg1 rescued astrocytic connexin43 (Cx43) downregulation in depression models, we investigated its brain-wide effects and molecular mechanisms in chronic unpredictable stress (CUS)-induced rats. Male rats subjected to CUS received Rg1 (40 mg· kg^-1 ·d^-1, i.g.) for 8 weeks. Multimodal neuroimaging (fMRI and PET/CT) revealed that Rg1 restored functional connectivity and ameliorated neuroinflammation in CUS rats, with the prelimbic area identified as a critical target region. Through integrated proteomic profiling, molecular docking, and surface plasmon resonance analyses, we pinpointed Cx43-mediated gap junction as the primary target underlying Rg1's therapeutic action. Mechanistically, we showed that Yes-associated protein (YAP), the primary effector of the Hippo pathway, was translocated into the nucleus to promote the expression of specific genes including those involved in inflammation. Notably, we demonstrated that Rg1 potentiated the Cx43-YAP interaction in the cytoplasm and restricted YAP nuclear translocation activity. The degradation of Cx43 and potentiation of YAP nuclear translocation might represent a novel mechanism for the pathogenesis of depression. Specific blockade of Cx43-based gap junctions, knockdown of Cx43 expression in primary cultured astrocytes, and conditional knockout of astrocytic Cx43 in mice promoted YAP nuclear translocation and retarded the antidepressant effects of Rg1. Accordingly, the Cx43-YAP connection may represent a potential therapeutic target for the antidepressant mechanism of Rg1.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1877-1891"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584234","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":"Inhibition of CDC27 O-GlcNAcylation coordinates the antitumor efficacy in multiple myeloma through the autophagy-lysosome pathway.","authors":"Hai-Qi Wu, Ren-Cai Qin, Wei-Jie Li, Jie-Na Liu, Chong Deng, Zi-Han Zheng, Jing-Peng Zheng, Yu Liu, Yan-Fang Meng, Chun Tang, Hong-Mei Tan, Fang-Fang Duan, Yuan Tang, Fan Xiao, Li-Wei Lu, Xiao-Yan Dai, Kong-Yang Ma","doi":"10.1038/s41401-025-01500-2","DOIUrl":"10.1038/s41401-025-01500-2","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a prevalent hematologic malignancy characterized by abnormal proliferation of cloned plasma cells. Given the aggressive nature and drug resistance of MM cells, identification of novel genes could provide valuable insights for treatment. In this study we performed machine learning in the RNA microarray data of purified myeloma plasma cell samples from five independent MM cohorts with 957 MM patients, and identified O-GlcNAcylation transferase (OGT) and cell division cycle 27 (CDC27) as the key prognostic genes for MM. We demonstrated a close link between OGT and CDC27 in MM cells by knockdown of OGT with siOGT, pharmacological inhibition of O-GlcNAcylation with OSMI-1 and pharmacological accumulation of O-GlcNAcylation with Thiamet G. Using mass spectrometry and immunoprecipitation, we identified the O-GlcNAcylated CDC27 protein as a key target protein that may be directly downregulated by OSMI-1 in MM.1S cells. We further revealed that O-GlcNAcylation maintained CDC27 protein stability by blocking the autophagy-lysosome pathway (ALP). Moreover, we demonstrated the enhanced antitumor efficacy of combined OSMI-1 and bortezomib (BTZ) treatment in MM cells both in vivo and in vitro. Thus, this study identifies a novel function of O-GlcNAcylation-related ALP in regulating CDC27 protein stability and a potential therapeutic strategy for treating MM.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2041-2055"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472144","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":"Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of Alzheimer's disease via modulating neuropathology and gut microbiota.","authors":"Mei Zhong, Qing-Qing Xu, Ming-Qing Huang, Ruo-Ting Zhan, Xiao-Qi Huang, Wen Yang, Zhi-Xiu Lin, Yan-Fang Xian","doi":"10.1038/s41401-025-01475-0","DOIUrl":"10.1038/s41401-025-01475-0","url":null,"abstract":"<p><p>Amyloid-beta (Aβ) aggregation, phosphorylated tau accumulation and neuroinflammation are considered as three hallmarks of Alzheimer's disease (AD). Rhynchophylline (RN), the major alkaloid of a Chinese medicinal plant Uncaria rhynchophylla, has been shown to possess potent anti-AD effects. This study explored the effects of RN on Aβ pathology, tauopathy, and neuroinflammation using three AD mouse models, including TgCRND8, 3×Tg-AD, and 5×FAD, with RN treatment lasting for 4, 6, and 6 months, respectively, followed by behavioral tests and biological assays. In addition, BV2 cells were employed to further evaluate the biological effects of RN. RN treatment improved cognitive functions by reducing anxiety-like behaviors, enhancing recognition ability, and ameliorating learning impairments. It modulated Aβ processing through reducing the Aβ-producing enzyme activities and enhancing degradation enzyme activities, thereby diminishing Aβ accumulation. RN also decreased hyperphosphorylated tau proteins at Thr181, Thr205, Ser396, and Ser404 sites. Moreover, RN diminished neuroinflammation by reducing microglia and astrocyte activation and lowering the release of inflammatory cytokines. Furthermore, RN treatment could restore gut microbiota dysbiosis in 5×FAD mice. In BV2 cells, knockdown of p53, HDAC2, and Galectin-3 markedly enhanced the anti-inflammatory effects of RN. Overall, the anti-AD properties of RN were attributed to its regulation of multiple biological pathways, including regulation of the p53/PINK1 signaling pathway, inhibition of the HDAC2/AMPK signaling pathway, suppression of the Galectin-3/C/EBPβ/AEP signaling pathway, and modulation of gut microflora dysbiosis. This pioneering study unambiguously revealed the effects of RN on cognitive impairments, APP processing, tauopathy, and neuroinflammation in different transgenic mouse models with differing AD burdens, highlighting its potential as an anti-AD therapeutic agent and enhancing the scientific basis for its clinical use in treating AD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1813-1833"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514332","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":"Selumetinib promotes coronary collateral circulation by inducing M2-like macrophage polarization following myocardial infarction.","authors":"Ke-Chuan Lin, Wei He, Dan Wang, Mei-Lian Yao, Jing Chen, Mei-Fang Chen, Guo-Gang Zhang, Chuan-Chang Li, Ling-Ping Zhu, Yong-Ping Bai","doi":"10.1038/s41401-025-01508-8","DOIUrl":"10.1038/s41401-025-01508-8","url":null,"abstract":"<p><p>Coronary collateral circulation (CCC) construction could be a practical therapeutic strategy for patients following myocardial infarction (MI), yet effective therapeutic drugs remain scarce. In this study we conducted database federation analyses to identify FDA-approved drugs that could promote CCC after MI injury. By comparing the differentially expressed genes in peripheral blood mononuclear cells (PBMCs) from two public gene profiles: one comparing patients with good versus poor CCC, and another with good versus poor heart function, the overlapped genes were analyzed using CMap, a popular resource designed for FDA approved drug. As a result, selumetinib emerged as a potential therapeutic drug to facilitate CCC formation. In MI mouse model induced by permanent ligation of left anterior descending (LAD) coronary artery, administration of selumetinib (2.5 mg/kg, i.p.) at the indicated time-points significantly enhanced CCC by promoting the polarization of macrophages from the pro-inflammatory M1-like phenotype to the pro-angiogenic M2-like phenotype, which was confirmed by 3D visualization through micro-CT imaging and immunofluorescent staining. We demonstrated that selumetinib (5 μM) promoted THP-1 differentiated into M2-like phenotype in vitro, and increased VEGFA secretion. Selumetinib-treated macrophages significantly enhanced in vitro angiogenesis of HUVECs in cocultured assay. We found that selumetinib (2.5 and 5 μM) dose-dependently inhibited the expression of the RIT1 in THP-1 derived M1 macrophage; knockdown of RIT1 significantly polarized M2-like phenotype via the MAPK/ERK1/2 signaling pathway, which was equal to the efficiency of selumetinib. In rescued experiments, specific overexpression of RIT1 in macrophage by injecting with targeting F4/80 promoter AAV9 in mice, could block the M2-like phenotype shifts and CCC formation by selumetinib. Finally, honokiol, a MAPK/ERK1/2 agonist was able to reverse the effects of selumetinib on CCC in mice with MI. In conclusion, selumetinib possesses therapeutic potential for induction of CCC formation after MI.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1905-1919"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584243","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":"PYRCR alleviates myocardial ischemia/reperfusion injury in mice via inhibiting DRG2-mediated cardiomyocyte pyroptosis.","authors":"Xin-Zhe Chen, Hong-Fei Xu, Xue-Mei Zhao, Fu-Hai Li, Jia-Hao Ren, Lu-Yu Zhou, Cui-Yun Liu, Yu-Qin Wang, Su-Min Yang, Fang Liu, Yu-Hui Zhang, Kun Wang, Xiang-Qian Gao","doi":"10.1038/s41401-025-01604-9","DOIUrl":"https://doi.org/10.1038/s41401-025-01604-9","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) are a distinct class of endogenous RNAs characterized by their covalently closed circular structure. CircRNAs play crucial regulatory roles in various biological processes and pathogenesis. In this study we investigated the role of circRNAs in cardiomyocyte pyroptosis and underlying mechanisms. Ischemia/reperfusion (I/R)-induced myocardial injury was induced in mice by ligation of the left anterior descending coronary artery (LAD). Neonatal mouse cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) assault. By using circRNA microarray, we found that the expression levels of a pyroptosis-related circRNA (designated PYRCR) were markedly decreased in H/R-exposed cardiomyocytes and I/R-injured mouse hearts. Overexpression of PYRCR inhibited cardiomyocyte pyroptosis, attenuated I/R-induced myocardial infarction and ameliorated cardiac function in mice. By RNA pull-down assays coupled with MS analysis followed by molecular validation, we identified developmental regulated GTP-binding protein 2 (DRG2) as the direct downstream target of PYRCR. Cardiac-specific DRG2 knockout mice displayed attenuated pyroptosis and enhanced cardiac function following I/R injury compared to DRG2^fl/fl controls. DRG2 directly bound to dynamin-related protein 1 (Drp1), the master regulator of mitochondrial fission, and enhanced its protein stability and expression. Importantly, PYRCR competitively disrupted the DRG2-Drp1 interaction, thereby suppressing DRG2-mediated Drp1 expression and subsequently reducing mitochondrial fission, cardiomyocyte pyroptosis, and myocardial damage. In conclusion, we demonstrate that PYRCR, a novel pyroptosis-related circRNA, protects against I/R-induced myocardial injury through the DRG2-mediated modulation of Drp1 activity, offering promising new therapeutic strategies for preventing cardiac damage mediated by cardiomyocyte pyroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525943","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":"SAAINT-DB: a comprehensive structural antibody database for antibody modeling and design.","authors":"Xiaoqiang Huang, Jun Zhou, Shuang Chen, Xiaofeng Xia, Y Eugene Chen, Jie Xu","doi":"10.1038/s41401-025-01608-5","DOIUrl":"https://doi.org/10.1038/s41401-025-01608-5","url":null,"abstract":"<p><p>Antibody (Ab) structures and antibody-antigen (Ag) interactions (AAIs) are essential for understanding immune recognition and designing Ab therapeutics. While existing structural Ab databases provide valuable insights, they still face limitations in data accuracy, completeness, and/or update frequency. Here, we present SAAINT-parser, a computational workflow for rapid, accurate, and robust extraction of Ab and AAI information from the Protein Data Bank (PDB). SAAINT-parser features precise detection of Ab chains, accurate pairing of Ab chains, and reliable identification of AAIs. The resulting SAAINT-DB, last updated on May 1, 2025, contains 19,128 data entries from 9757 PDB structures, offering a comprehensive and up-to-date resource. Detailed analyses highlight the advantages of SAAINT-DB over the widely used SAbDab in terms of data accuracy and completeness. Furthermore, SAAINT-DB provides nearly twice as many non-redundant, manually curated Ab-Ag binding affinity entries as SAbDab. To support Ab-related research and benefit the broader scientific community, we provide open access to SAAINT-parser, the SAAINT-DB summary file, unprocessed PDB structures, and SAAINT-parser-processed structure models at https://github.com/tommyhuangthu/SAAINT .</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525944","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}