Acta Pharmacologica Sinica最新文献

{"title":"GRK2-mediated phosphorylation and de-succinylation of PKM2 reduce macrophage glycolysis in rheumatoid arthritis.","authors":"Xue-Zhi Yang, Wan-Kang Zhang, Zi-Qing Zhu, Wei Zhao, Ling-Li Luo, Lu-Ping Wang, Ying-Jie Zhao, Yan Chang, Wei Wei","doi":"10.1038/s41401-025-01582-y","DOIUrl":"10.1038/s41401-025-01582-y","url":null,"abstract":"<p><p>Glucose metabolism disorder is an important hallmark of rheumatoid arthritis (RA). Inhibiting key glycolysis enzymes is the primary approach, but effective treatments targeting glycolytic metabolism have not yet reached clinical practice. G protein-coupled receptor kinase 2 (GRK2) as a multi-signals regulatory hub has attracted wide attention. In this study, we investigated the role of GRK2 inhibitor on glycolysis of monocyte-derived macrophages (MDMs), the primary source of inflammatory mediators in RA synovium. Human peripheral mononuclear cells were obtained from RA patients and differentiated into MDMs with M-CSF (100 ng/ml) for 5 days. By analyzing the metabolic status of RA MDMs in normoxia and hypoxia, we found that glycolysis was increased in RA MDMs, and inhibiting glycolysis could suppress the macrophage inflammatory phenotype. The antiglycolytic role of GRK2 deletion was tested in MDMs in vitro and in vivo. We conducted proteomics and mass spectrometric analysis and confirmed the inhibitory role of GRK2 on several key glycolytic enzymes. GRK2 maintained PKM2 tetramer stability through two synergistic modifications-phosphorylation at S406 and de-succinylation at K433. In RA, decreased cytoplasmic GRK2 protein levels impaired its regulation toward PKM2, leading to enhanced glycolysis and accelerating RA progression. Administration of GRK2 inhibitors paroxetine, CP-25, or the glycolysis inhibitor 2-DG for 21 days in the CIA mouse model all restored cytoplasmic GRK2 levels and homeostatic regulation, offering a potential therapeutic approach for RA glycolysis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2693-2706"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155411","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":"OTUD1 deficiency attenuates myocardial ischemia/reperfusion induced cardiomyocyte apoptosis by regulating RACK1 phosphorylation.","authors":"Yue Luo, Wei-Xin Li, Qing-Song Zheng, Jue-Qian Yan, Yu-Die Yang, Si-Rui Shen, Qian-Hui Zhang, Guang Liang, Yi Wang, Ding-Dao Chen, Xiang Hu, Wu Luo","doi":"10.1038/s41401-025-01567-x","DOIUrl":"10.1038/s41401-025-01567-x","url":null,"abstract":"<p><p>Myocardial infarction (MI) is an important risk factor of cardiovascular disease (CVD) and its incidence has been on the rise globally. Myocardial ischemia/reperfusion (I/R) injury is frequently detected in the ischemic myocardium. Recent studies have shown that ubiquitination plays an important role in the cardiac pathophysiological processes. Herein, we investigated the role and molecular mechanism of Ovarian tumor deubiquitinase 1 (OTUD1) in I/R induced myocardial injury. It was observed that the myocardial OTUD1 was upregulated in I/R-induced heart tissues and global deletion of OTUD1 significantly ameliorated I/R induced myocardial injury and dysfunction. Similarly, silencing or overexpression OTUD1 affected the hypoxia/reoxygenation (H/R) induced cell apoptosis in cultured cardiomyocytes. Mechanistically, immunoprecipitation-mass spectrometry revealed that OTUD1 directly bound to receptor for activated C-kinase 1 (RACK1) which has been identified as a scaffold protein for multiple kinases including mitogen-activated protein kinase (MAPKs) and Inhibitor of nuclear factor kappa B kinase (IKK). OTUD1 could cleave K63-linked polyubiquitin chains to enhance RACK1 phosphorylation, thus modulating MAPKs and nuclear factor kappa B (NF-κB) signaling. Finally, silencing of RACK1 reverses OTUD1-promoted H/R induced myocardial apoptosis. In conclusion, our findings suggest that OTUD1 promotes I/R-induced heart injury by deubiquitinating RACK1, suggesting that OTUD1 is a potential therapeutic target for myocardial I/R.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2649-2662"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109277","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":"Yuanhuacine suppresses head and neck cancer growth by promoting ASCT2 degradation and inhibiting glutamine uptake.","authors":"Xin-Yi Chen, Xin Chen, Xiao-Hui Liang, Dong Lu, Rong-Rong Pan, Qing-Yi Xiong, Xiao-Xia Liu, Jia-Yi Lin, Li-Jun Zhang, Hong-Zhuan Chen, Jin-Mei Jin, Wei-Dong Zhang, Xin Luan","doi":"10.1038/s41401-025-01562-2","DOIUrl":"10.1038/s41401-025-01562-2","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) cells exhibit a high dependency on glutamine metabolism, making it an attractive target. Despite the well-established link between glutamine reliance and tumor progression, the specific role of glutamine transporters in HNSCC remains poorly understood. The alanine-serine-cysteine transporter 2 (ASCT2), a key glutamine transporter, is overexpressed in HNSCC, and its silencing has been shown to reduce intracellular glutamine and glutathione levels, inhibiting tumor growth. These facts suggest that targeting ASCT2-mediated glutamine uptake could offer a promising therapeutic strategy for HNSCC. But no clinically approved drugs directly target ASCT2, and challenges such as the limited stability of antisense oligonucleotides persist. In this study we evaluated the correlation between ASCT2-mediate glutamine metabolism and its impact on HNSCC patients. We established a virtual screening method followed by cytotoxic assays to identify small molecules that specifically target ASCT2. Among the top 15 candidates, we identified yuanhuacine (YC) as the most potent antitumor compound with IC₅₀ values of 1.43, 6.62, and 6.46 μM against HN6, CAL33, and SCC7 cells, respectively. We demonstrated that YC (0.3-5 μM) dose-dependently induced ASCT2 degradation by recruiting the E3 ubiquitin ligase RNF5, inhibiting glutamine uptake in HN6 cells. This disruption led to mitochondrial dysfunction and enhanced the therapeutic efficacy of YC. Our results highlight YC as a promising regulator of ASCT2-mediated glutamine metabolism in HNSCC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2779-2792"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075261","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":"STING inhibits the progression of esophageal squamous cell carcinoma by suppressing CPT1A-mediated fatty acid β-oxidation.","authors":"Lei Zhang, Ling-Jun Zhu, Yuan Zhao, Xin-Yuan Lei, Dan-Hui Wu, Kai-Yue He, Meng-Jie Liu, Jing-Yu Yang, Jin-Rong Guo, Zhi-Hao Jiang, Zhen-Hua Yan, Zhi-Xiang Xu, Yong-Ping Jian","doi":"10.1038/s41401-025-01581-z","DOIUrl":"10.1038/s41401-025-01581-z","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) is characterized by high aggressiveness and poor prognosis. Metabolic reprogramming is a hallmark of ESCC, with lipid metabolism frequently upregulated. It has been shown that lipid metabolism, particularly fatty acid β-oxidation (FAO), plays an essential role in energy homeostasis, membrane biosynthesis, and tumor progression. Stimulator of interferon genes (STING), a key innate immune signaling molecule, also acts as a metabolic checkpoint by inhibiting hexokinase 2, thereby limiting aerobic glycolysis and enhancing anti-tumor immune responses. In this study, we investigated the impact of STING on FAO and tumorigenesis in ESCC. We showed that the expression levels of STING were significantly reduced in ESCC compared to adjacent normal tissue. In the ESCC cell line KYSE-510, knockdown of STING significantly elevated lipid metabolites, decreased intracellular lipid droplets, and increased FAO products, whereas overexpression of STING inhibited ESCC cell proliferation and tumor progression by suppressing FAO. Targeted lipid metabolomic analyses revealed that STING interacted with carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in FAO. STING promoted the ubiquitination and degradation of CPT1A by disrupting its interaction with USP15, a deubiquitinating enzyme. Treatment with the CPT1A inhibitor etomoxir (50 μM) reversed the increased FAO induced by STING depletion in KYSE-30 cells. In both in vitro and in vivo models, supplementation with palmitic acid rescued STING-induced growth inhibition, restoring tumor cell growth. In addition, STING knockout in 4-NQO-induced ESCC mice led to accelerated tumor progression, which could be mitigated by CPT1A inhibition. Our results suggest that reduced STING expression enhances FAO and promotes ESCC cell proliferation, implicating FAO suppression as a potential therapeutic strategy for ESCC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2793-2807"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109346","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":"Dehydrotrametenolic acid methyl ester, a triterpenoid of Poria cocos, alleviates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation via targeting Caspase-1 in mice.","authors":"Ling-Yan Xia, Nai-Rong Yu, Su-Ling Huang, Hui Qu, Li Qin, Qin-Shi Zhao, Ying Leng","doi":"10.1038/s41401-025-01569-9","DOIUrl":"10.1038/s41401-025-01569-9","url":null,"abstract":"<p><p>Non-alcoholic steatohepatitis (NASH) has emerged as a prevalent chronic liver disease with a huge unmet clinical need. A few studies have reported the beneficial effects of Poria cocos Wolf (P. cocos) extract on NASH mice, but the active components were still unknown. In this study we investigated the therapeutic effects of dehydrotrametenolic acid methyl ester (ZQS5029-1), a lanosterol-7,9(11)-diene triterpenes in P. cocos, in a high-fat diet plus CCl₄ induced murine NASH model and a GAN diet induced ob/ob murine NASH model. The NASH mice were treated with ZQS5029-1 (75 mg·kg^-1·d^-1, i.g.) for 6 and 8 weeks, respectively. We showed that ZQS5029-1 treatment markedly relieved liver injury, inflammation and fibrosis in both the murine NASH models. We found that ZQS5029-1 treatment significantly suppressed hepatic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in both the NASH murine models, and blocked lipopolysaccharides (LPS)+adenosine 5'-triphosphate (ATP)/Nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) and Kupffer cells in vitro. We demonstrated that ZQS5029-1 directly bound to the H236 residue of mouse Caspase-1, thereby inhibiting NLRP3 inflammasome activation. The effects of ZQS5029-1 on macrophage-hepatocyte/HSC crosstalk were analyzed using the supernatants from macrophages preconditioned with LPS + ATP introduced into hepatocytes and hepatic stellate cells (HSCs). We found that the conditioned medium from the BMDMs induced injury and death, as well as lipid accumulation in hepatocytes, and activation of HSCs; these effects were blocked by conditioned medium from BMDMs treated with ZQS5029-1. Moreover, the protective effects of ZQS5029-1 on hepatocytes and HSCs were eliminated by H236A-mutation of Caspase-1. We conclude that ZQS5029-1 is a promising lead compound for the treatment of NASH by inhibiting NLRP3 inflammasome activation through targeting Caspase-1 and regulating the macrophage-hepatocyte/HSC crosstalk.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2734-2750"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957339","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":"Fangchinoline-mediated autophagy inhibition amplifies antigen presentation and PD-1 blockade efficacy in lung cancer.","authors":"Yue Song, Yu-Xiao Jiang, Jie-Ying Guan, Jun-Bo Jiang, Man-Si Xu, Xue-Ying Zhong, Li-Na He, Zhen-Yang Ren, Yuan Liao, Fang Liu, Yan-Jun Jiang, Shan Hu, Wei Guo, Ting-Xiu Zhao, Xiao-Yi Liu, Jiang-Yong Gu, Ya-Fei Shi, Huan-Huan Luo, Kun Wang, Jian-Yong Xiao","doi":"10.1038/s41401-025-01541-7","DOIUrl":"10.1038/s41401-025-01541-7","url":null,"abstract":"<p><p>Cancer cells frequently exhibit MHC-I deficiency, impairing immune-mediated cytotoxicity even in the presence of PD-1 checkpoint inhibition. To date, no clinically approved therapies exist that can upregulate MHC-I expression to boost immune responses against cancer cells. Emerging evidence has shown that autophagy plays a role in MHC-I molecule degradation, contributing to reduced recognition of cancer cells by CD8⁺ T cells. We previously report that fangchinoline, a bisbenzylisoquinoline alkaloid derived from Chinese herb, is a novel autophagy inhibitor with an adjuvant of chemotherapy against lung cancer. In this study we investigated the modulatory effects of PD-1 blockade combined with fangchinoline on CD8⁺ T cells within the tumor microenvironment of lung cancer. We showed an inverse correlation between elevated autophagic activity and decreased MHC-I surface expression-a phenomenon often associated with poor clinical efficacies-in various human lung cancer cell lines (NCI-H1299, NCI-H1975, A549, NCI-H1650 and NCI-H446) compared with normal bronchial epithelial cells lung cancer. Knockdown of ATG4 and ATG5 resulted in increased MHC-I expression and enhanced tumor antigen presentation in NCI-H1975, NCI-H1299 and A549 cells. As autophagy receptors were crucial for transporting proteins to autophagosomes for degradation, we sequentially silenced various autophagy receptors and found that NDP52 knockdown specifically restored MHC-I expression, suggesting that NDP52-mediated autophagy might contribute to MHC-I degradation, and autophagy inhibition might enhance immune-mediated cancer cell death. We showed that pretreatment of LLC-OVA cells with the autophagy inhibitor fangchinoline (1.25, 2.5, 5 μM) followed by coculture with CD8⁺ T cells, dose-dependently enhanced immune killing. In both in vitro and in vivo experiments, we showed that fangchinoline combined with anti-PD-1 therapy significantly increased CD8⁺ T cell-mediated cytotoxicity. In conclusion, this study highlights NDP52 as a key autophagy receptor involved in MHC-I degradation and provides a new insight into tumor immune evasion. Combining autophagy inhibition with immunotherapy may be a promising therapeutic strategy for anticancer immunity enhancement.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2751-2764"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958388","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":"PXR ribosylation at E194 amplifies NAPQI in acetaminophen‒induced liver injury in mice, rescued by Schisandrin B.","authors":"Jia-Chan Long, Chen-Xu Liu, Meng-Yao Wang, Cai-Hong Liu, Fan Zhang, Zhong-Qiu Liu, Lin An, Cai-Yan Wang","doi":"10.1038/s41401-025-01632-5","DOIUrl":"https://doi.org/10.1038/s41401-025-01632-5","url":null,"abstract":"<p><p>Acetaminophen (APAP)-induced acute liver injury (AILI) is primarily driven by CYP3A4‒mediated overproduction of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), CYP3A4 activity serves as the rate-limiting determinant of NAPQI accumulation levels. Poly ADP-ribose polymerase 1 (PARP1)-driven ribosylation, a posttranslational modification, has been linked to drug-induced liver injury. PARP1 interacts with pregnane X receptor (PXR), a nuclear receptor that regulates drug-metabolizing enzymes including CYP3A4. In this study we investigated the specific sites of PARP1-mediated PXR ribosylation, particularly regarding their functional relevance to CYP3A4-driven NAPQI biosynthesis in AILI. To establish AILI models, mice were injected with APAP (300 mg·kg^-1, i.p.), liver tissues and serum were collected for analysis 24 h post-injection. In vitro study was conducted in primary hepatocytes isolated from AILI mice and in human hepatic L02 cells exposed to APAP (5, 10, 20 μM). We demonstrated that under AILI conditions, PARP1 catalyzed ribosylation of PXR at the residue E194, forming a PARP1-PXR‒CYP3A4 regulatory axis that amplified oxidative stress and NAPQI accumulation through a positive feedback loop. Specifically, PARP1 was significantly overexpressed in AILI models in vivo and in vitro, and its interaction with PXR was confirmed in immunoprecipitation and proximity biotinylation assays. Molecular dynamics (MD) simulations, mass spectrometry and E194A site-directed mutagenesis revealed that PARP1-mediated ribosylation of PXR E194 enhanced CYP3A4 transcription, ultimately leading to excessive NAPQI production. MD simulations also identified a natural compound schisandrin B (Sch B) that specifically bound to the ligand-binding domain of PXR, induced conformational changes and disrupted the PARP1-PXR interaction interface, thus suppressed the ribosylation. In AILI murine models, administration of Sch B (25, 50, and 100 mg·kg^-1·d^-1, i.g.) for 8 days significantly reduced serum ALT and AST levels, attenuated oxidative stress, and inhibited NAPQI generation by blocking complex formation. This study not only elucidates the mechanisms of PARP1-mediated PXR E194 ribosylation in AILI but also identifies Sch B as the first specific inhibitor of this pathway, providing a theoretical basis for precision detoxification strategies targeting posttranslational modifications.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205269","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":"Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia.","authors":"Shu-Qing Chu, Yi-Jie Chen, Rui-Rui Yang, Dan Teng, Gui-Zhen Zhou, Ying-Ying Zhang, Bu-Ying Niu, Jia-Hang Xu, Ke-Xin Lin, Xin-Yu Yang, Xu-Tong Li, Ming-Yue Zheng, Su-Lin Zhang","doi":"10.1038/s41401-025-01657-w","DOIUrl":"https://doi.org/10.1038/s41401-025-01657-w","url":null,"abstract":"<p><p>Hypoxia-inducible factor 2-alpha (HIF-2α), a critical transcription factor, forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) to drive the transcription of erythropoietin (EPO), a key regulator of erythropoiesis. Activation of this pathway plays a pivotal role in the treatment of anemia. By discovered structure-based virtual screening and pharmacological assays, we herein discovered an amide thiazole AT-1 that bound to HIF-2α with a K_D of 2.63 μM, and enhanced the stability of the HIF-2α-ARNT heterodimer. Molecular docking and site-directed mutagenesis analysis revealed the critical roles of His293 and Tyr307 in the binding of AT-1 to HIF-2α. Pharmacological studies showed that AT-1 (10, 20, 40 μM) dose-dependently enhanced both the transcription and secretion of EPO in 786-O and Hep3B cells. In zebrafish (Danio rerio), AT-1 (10 or 50 μM) exhibited favorable safety profiles and, when combined with the prolyl hydroxylase (PHD) inhibitor Molidustat (10 μM), effectively mitigated doxorubicin-induced anemia. In adenine-induced chronic kidney disease (CKD) mouse model, combined administration of AT-1 (50 mg·kg^-1·d^-1, i.p.) and Molidustat (10 mg·kg^-1·d^-1, i.p.) for 15 days produced stronger effects on increasing EPO levels and alleviating anemia than Molidustat alone, further supporting the therapeutic potential of AT-1 in CKD-related anemia.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205271","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":"ROS-induced degradation of hERG potassium channels contributes to aripiprazole-induced prolongation of the QTc interval.","authors":"Yu-Hong Cao, Xiao-Chen Wang, Hong-Kun Wang, Zong-Kuai Yang, Dan-Dan Liu, Yang Yang, Rong Kuang, Ping Liang","doi":"10.1038/s41401-025-01648-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01648-x","url":null,"abstract":"<p><p>As antipsychotic administration often persists for a lifetime, antipsychotic-induced cardiotoxicity (AIC) becomes a significant and potentially life-threatening side effect. Owing to the lack of an appropriate human cardiomyocyte experimental model, current research on AIC is primarily based on clinical case reports. In this study, we generated human iPSC-derived cardiomyocytes (iPSC-CMs) and characterized the cardiotoxicity of 6 antipsychotics (clozapine, haloperidol, quetiapine, olanzapine, risperidone, and aripiprazole) used in clinical practice. Multielectrode array analysis revealed that all 6 antipsychotics, when used within their respective clinical plasma concentration (CPC) ranges, were likely to cause a significantly prolonged field potential duration (FPD) in iPSC-CMs. Moreover, administration of the third-generation antipsychotic aripiprazole (10 mg/kg, i.g.) led to marked QT interval prolongation in beagle dogs. We demonstrated that aripiprazole administration resulted in mitochondrial damage and oxidative stress, which accelerated protein degradation of human ether-à-go-go-related gene (hERG) channels, generating a rapid delayed rectifying potassium current (I_Kr) through the proteasome pathway, ultimately leading to FPD prolongation. Scavenging reactive oxygen species or suppressing the ubiquitin‒proteasome pathway (UPP) significantly restored hERG channel function and rescued the prolonged FPD phenotype in aripiprazole-treated iPSC-CMs. Our results suggest that caution should be taken when aripiprazole is prescribed to high-risk patients with preexisting comorbidities. Manipulation of excessive oxidative stress or suppression of the UPP may offer novel therapeutic strategies for mitigating aripiprazole-induced proarrhythmic risk.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205284","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":"Targeting the interactions between neutrophils and microglia: a novel strategy for anti-inflammatory treatment of stroke.","authors":"Long-Rui Wang, Zi-Yuan Zhao, Zhao-Wei Li, Yin-Ru Jiang, Wen-Jing Sun, Guan-Hua Du, Rui-Li Shi, Ling-Lei Kong","doi":"10.1038/s41401-025-01662-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01662-z","url":null,"abstract":"<p><p>Stroke is the second leading cause of mortality and the leading cause of adult disability worldwide. Neuroinflammation is a crucial mechanism that regulates the pathogenesis and prognosis of stroke and involves both peripheral and intracerebral immune cells. Neutrophils and microglia are the primary immune cells that mediate neuroinflammation and play bidirectional roles after stroke. Significant interactions between neutrophils and microglia exist. Microglia regulate the activation, infiltration, as well as formation of neutrophil extracellular traps (NETs), whereas neutrophils regulate the polarization and phagocytic activity of microglia. In this review, we summarize the bidirectional roles of neutrophils and microglia in stroke with an emphasis on the interactions between neutrophils and microglia, as well as the associated signaling pathways and targets involved. We further introduce potential stroke treatment drugs that regulate the interactions between neutrophils and microglia, including anti-inflammatory drugs and natural products. We propose that, according to the different ischemic times and cell activation states, regulating the interactions between neutrophils and microglia through relevant targets and signaling pathways may be an ideal strategy for the anti-inflammatory treatment of stroke, potentially improving treatment and prognosis of stroke. This review summarizes the bidirectional roles of neutrophils and microglia in stroke, respectively, focusing on the interactions and signaling pathways between neutrophils and microglia, as well as potential therapeutic targets and drugs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205293","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}