Acta Pharmacologica Sinica最新文献_第5页

Dynamic centrosomes: functional diversity and remodeling across cell types. 动态中心体：跨细胞类型的功能多样性和重塑。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-29 DOI: 10.1038/s41401-026-01935-1

Ning Ju, Hui-Jie Zhu, Jia-Rui Shi, Jin-Min Gao, Fei-Fei Qi

{"title":"Dynamic centrosomes: functional diversity and remodeling across cell types.","authors":"Ning Ju, Hui-Jie Zhu, Jia-Rui Shi, Jin-Min Gao, Fei-Fei Qi","doi":"10.1038/s41401-026-01935-1","DOIUrl":"https://doi.org/10.1038/s41401-026-01935-1","url":null,"abstract":"The centrosome is an evolutionarily conserved, microtubule-based organelle that has pronounced cell type-specific functions. In somatic cells, it serves as the primary microtubule-organizing center (MTOC), regulating chromosome segregation and contributing to asymmetric cell division and ciliogenesis. Although traditionally considered structurally stable, increasing evidence indicates that centrosomes can undergo extensive remodeling or even complete elimination in specialized cell types. Recent studies have begun to elucidate the molecular basis of these processes. For example, during oogenesis, CDK1-mediated phosphorylation of SAS-6 disrupts its phase separation, thus promoting cartwheel disassembly and centriole elimination. Building on these advances, this review summarizes the dynamic behaviors and fates of centrosomes across diverse cell types, with a particular focus on oogenesis, spermatogenesis, and neurodevelopment, and discusses the emerging molecular mechanisms that regulate centrosome remodeling. We further highlight the potential links between dysregulated centrosome dynamics and human diseases, including cancer, neurodevelopmental disorders, and infertility, and discuss centrosome regulators as potential therapeutic targets. A deeper understanding of centrosome dynamics is expected to provide new insights into both fundamental cell biology and the development of targeted interventions.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073146","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

Targeting iRhom2-mediated PANoptosis ameliorates acute kidney injury. 靶向irhom2介导的PANoptosis可改善急性肾损伤。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-29 DOI: 10.1038/s41401-026-01936-0

Hong-Shen Lu, Qing-Sheng Han, Dan-Dan Ren, Ying-Ying Liu, Shun Yu, Ming-Bo Zheng, Ji-Chao Wu, Xiao-Jie Wang, Rong-Kun Li, Ran Ji, Zhi-Yong Liu, Zi-Ying Wang, Yu Sun, Min Liu, Meng Zhou, Gui-Mei Lin, Wei Tang, Yan Zhang, Fan Yi

{"title":"Targeting iRhom2-mediated PANoptosis ameliorates acute kidney injury.","authors":"Hong-Shen Lu, Qing-Sheng Han, Dan-Dan Ren, Ying-Ying Liu, Shun Yu, Ming-Bo Zheng, Ji-Chao Wu, Xiao-Jie Wang, Rong-Kun Li, Ran Ji, Zhi-Yong Liu, Zi-Ying Wang, Yu Sun, Min Liu, Meng Zhou, Gui-Mei Lin, Wei Tang, Yan Zhang, Fan Yi","doi":"10.1038/s41401-026-01936-0","DOIUrl":"https://doi.org/10.1038/s41401-026-01936-0","url":null,"abstract":"Although PANoptosis plays a pivotal role in the pathogenesis of acute kidney injury (AKI), the underlying regulatory mechanisms and effective therapeutic strategies remain largely unexplored. In this study, we report a novel function of inactive rhomboid 2 (iRhom2), encoded by the Rhbdf2 gene, in promoting PANoptosis in tubular epithelial cells (TECs). First, iRhom2 expression was induced in the kidneys of mice with ischemia/reperfusion injury (IRI) or cisplatin-induced AKI, which was further confirmed in the kidneys of patients with biopsy-proven acute tubular necrosis (ATN). Moreover, iRhom2 levels positively correlated with serum creatinine (SCr) and blood urea nitrogen (BUN) levels in ATN patients. Functionally, the tubule-specific deletion of Rhbdf2 alleviated AKI progression. Mechanistically, iRhom2 facilitated the trafficking of ATF6 from the endoplasmic reticulum (ER) to the Golgi apparatus, leading to its proteolytic cleavage. Then, cleaved ATF6 (cATF6) subsequently translocated to the nucleus and upregulated the expression of HSP90, which acts as a positive regulator of IFN regulatory factor 1 (IRF-1), thereby promoting the formation of the RIPK1 PANoptosome in TECs. Importantly, both the silencing of Rhbdf2 using neutrophil membrane-enveloped nanoparticles and the pharmacological inhibition of iRhom2 with sulforaphane alleviated renal damage in AKI model mice. Collectively, these results reveal iRhom2 as a key regulator of PANoptosis and suggest that targeting iRhom2 may represent a potential therapeutic strategy for AKI.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079392","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

LRRC8A deficiency in vascular smooth muscle cells promotes STAT1/Calcrl/Ramp1 signaling to decrease blood pressure. 血管平滑肌细胞缺乏LRRC8A可促进STAT1/Calcrl/Ramp1信号传导降低血压。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-22 DOI: 10.1038/s41401-026-01929-z

Feng-Ting Lu, Xiao-Fei Lv, Zhu-Jun Liang, Wei Tang, Wen-Yi Lai, Gui-Yong Yang, Yan-Shan Li, Yan-Jun Mu, Yu-Bo Tang, Hui-Kun Xing, Zhong-Han Yang, Yong-Yuan Guan, Jia-Guo Zhou, Jian-Hui Chen, Kai-Min Guo, Si-Jia Liang, Ming-Ming Ma

{"title":"LRRC8A deficiency in vascular smooth muscle cells promotes STAT1/Calcrl/Ramp1 signaling to decrease blood pressure.","authors":"Feng-Ting Lu, Xiao-Fei Lv, Zhu-Jun Liang, Wei Tang, Wen-Yi Lai, Gui-Yong Yang, Yan-Shan Li, Yan-Jun Mu, Yu-Bo Tang, Hui-Kun Xing, Zhong-Han Yang, Yong-Yuan Guan, Jia-Guo Zhou, Jian-Hui Chen, Kai-Min Guo, Si-Jia Liang, Ming-Ming Ma","doi":"10.1038/s41401-026-01929-z","DOIUrl":"https://doi.org/10.1038/s41401-026-01929-z","url":null,"abstract":"Blood pressure (BP) is positively correlated with the activity of volume-regulated chloride channels (VRCCs) in vascular smooth muscle cells (VSMCs) during hypertension, and LRRC8A has recently been identified as the key molecular component of VRCCs. However, the role of LRRC8A in BP regulation remains unclear. Here, we generated SMC-specific LRRC8A knockout (CKO) mice and performed bulk RNA-sequencing, ChIP-sequencing, and coimmunoprecipitation coupled with mass spectrometry to elucidate the underlying mechanisms. We found that systolic BP was largely reduced in CKO mice under basal conditions as well as in those with angiotensin II- or DOCA-salt-induced hypertension. Aortas from CKO mice exhibited decreased vasoconstriction, whereas vasodilation and cardiac function remained unaffected. Mechanistically, LRRC8A deletion reduced STAT1 degradation and enhanced Calcrl transcription, thereby strengthening the inhibitory effect of Calcrl on myosin light chain phosphorylation and identifying LRRC8A deficiency as a negative regulator of VSMC contractility. Moreover, LRRC8A deficiency promoted the interaction between CSRP2 and PIAS1 and subsequently suppressed STAT1 degradation. Pharmacological inhibition of STAT1 with fludarabine abolished the protective effects of LRRC8A deficiency against hypertension and vasoconstriction. In summary, our findings reveal an essential role for LRRC8A in BP regulation and highlight a potential therapeutic strategy for hypertension.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023652","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

Niclosamide suppresses breast cancer progression and enhances paclitaxel sensitivity by targeting the ATP6AP1-YY1-XIAP axis. 奈洛沙胺通过靶向ATP6AP1-YY1-XIAP轴抑制乳腺癌进展并增强紫杉醇敏感性。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-22 DOI: 10.1038/s41401-026-01921-7

Xin-Yuan Sun, Xiao-Ya Wan, Shi-Jun Cao, Rong Gong, Shi-Long Jiang, Yi-Zhi Li, Yi-Ning Cheng, Yun-Gui Li, Ting Jiang, Zhong-Yuan Xiang, Yan Cheng

{"title":"Niclosamide suppresses breast cancer progression and enhances paclitaxel sensitivity by targeting the ATP6AP1-YY1-XIAP axis.","authors":"Xin-Yuan Sun, Xiao-Ya Wan, Shi-Jun Cao, Rong Gong, Shi-Long Jiang, Yi-Zhi Li, Yi-Ning Cheng, Yun-Gui Li, Ting Jiang, Zhong-Yuan Xiang, Yan Cheng","doi":"10.1038/s41401-026-01921-7","DOIUrl":"https://doi.org/10.1038/s41401-026-01921-7","url":null,"abstract":"ATP6AP1, a key accessory subunit of the vacuolar H+-ATPase (V-ATPase) complex responsible for organelle acidification, has emerged as a potential cancer driver. Numerous studies have shown that ATP6AP1 is significantly upregulated in breast cancer, and its high expression is associated with poor prognosis. However, the specific functions and underlying mechanisms of ATP6AP1 in breast cancer progression remain unclear. In the present study, ATP6AP1 was demonstrated to enhance the malignant phenotype of breast cancer cells by upregulating XIAP expression. YY1 was further identified as a novel transcription factor that regulates XIAP, and ATP6AP1 was shown to directly interact with YY1, thereby stabilizing YY1 protein levels and subsequently promoting XIAP expression. In addition, ATP6AP1 silencing markedly increased the sensitivity of breast cancer cells to paclitaxel. Through screening of an FDA-approved drug library, niclosamide was identified as a novel degrader of ATP6AP1. Niclosamide bound to ATP6AP1, reduced its protein stability, and consequently downregulated its expression. Moreover, niclosamide inhibited the proliferation, migration, and invasion of breast cancer cells while promoting apoptosis through targeted degradation of ATP6AP1. Furthermore, niclosamide significantly enhanced the sensitivity of breast cancer cells to paclitaxel by targeting the ATP6AP1-YY1-XIAP axis. Taken together, these findings demonstrated that ATP6AP1 promotes breast cancer progression through activation of the YY1-XIAP signaling axis. Niclosamide was also identified as a promising therapeutic agent targeting ATP6AP1, thereby providing a potential therapeutic strategy for breast cancer treatment.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023597","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

Advances in the role of astrocytes in glioma progression and therapy. 星形胶质细胞在胶质瘤进展和治疗中的作用研究进展。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-22 DOI: 10.1038/s41401-026-01934-2

Xiao-Hong Xu, Ran Wu, Jun Fan, Xiao-Qian Chen

{"title":"Advances in the role of astrocytes in glioma progression and therapy.","authors":"Xiao-Hong Xu, Ran Wu, Jun Fan, Xiao-Qian Chen","doi":"10.1038/s41401-026-01934-2","DOIUrl":"https://doi.org/10.1038/s41401-026-01934-2","url":null,"abstract":"Glioblastoma is the most common malignant primary intracranial tumor, characterized by high invasiveness, rapid progression, and poor sensitivity to radiotherapy and chemotherapy. Given the limited efficacy of current treatments, novel therapeutic strategies are urgently needed. Astrocytes play pivotal roles in glioma initiation and progression by promoting tumor proliferation, invasion, therapeutic resistance, and immune evasion. Reactive astrocytes are increasingly recognized as dynamic, heterogeneous cell states rather than fixed subtypes. This review discusses representative astrocyte programs linked to immune modulation, tumor support, and therapy response, including TRAIL-associated, STAT3/CHI3L1-related, and PDGFR-β-associated phenotypes. Furthermore, the study describes emerging astrocyte-targeted strategies, such as blocking pro-tumor cytokine signaling, disrupting astrocyte-glioma communication, inhibiting extracellular vesicle transfer, and modulating immunosuppressive astrocyte states. Targeting tumor-associated astrocytes may offer new strategies to counter glioblastoma progression, immune escape, and therapeutic resistance.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023613","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

Tectorigenin alleviates HFpEF by targeting the EGFR-EGR2-Acot1 axis to improve myocardial lipid metabolism. 鸢尾黄素通过靶向EGFR-EGR2-Acot1轴改善心肌脂质代谢来缓解HFpEF。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-18 DOI: 10.1038/s41401-026-01926-2

Li-Guo Wang, Ke Lin, Meng-Zhen You, Qin-Feng Li, Wen-Jie Wei, Hui Li, Yi Shi, Yu-Feng Yan, Ran Li, Mei-Hui Wang, Chun-Lei Xia, Guo-Sheng Fu, Ya-Ting Xu

{"title":"Tectorigenin alleviates HFpEF by targeting the EGFR-EGR2-Acot1 axis to improve myocardial lipid metabolism.","authors":"Li-Guo Wang, Ke Lin, Meng-Zhen You, Qin-Feng Li, Wen-Jie Wei, Hui Li, Yi Shi, Yu-Feng Yan, Ran Li, Mei-Hui Wang, Chun-Lei Xia, Guo-Sheng Fu, Ya-Ting Xu","doi":"10.1038/s41401-026-01926-2","DOIUrl":"https://doi.org/10.1038/s41401-026-01926-2","url":null,"abstract":"Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of all heart failure cases worldwide, yet effective targeted therapies remain limited. Tectorigenin (Tec), a bioactive isoflavone derived from traditional Chinese medicine, exhibits diverse cardioprotective effects; however, its therapeutic potential and underlying mechanisms in HFpEF remain incompletely understood. This study aimed to investigate the effects of Tec on HFpEF and elucidate the underlying molecular mechanisms. A mouse model of HFpEF was established using the \"two-hit\" approach (high-fat diet + L-NAME). In vivo experiments included echocardiography, histological staining, treadmill testing, metabolic assessments, and molecular analyses. In vitro, neonatal rat ventricular myocytes (NRVMs) exposed to palmitic acid (PA) were used to model cardiomyocyte lipotoxicity. RNA sequencing, network pharmacology, molecular docking, surface plasmon resonance, pull-down assays, chromatin immunoprecipitation, and gene silencing were employed to elucidate the regulatory mechanisms. Tec attenuated HFpEF progression and retained therapeutic efficacy when administered after HFpEF establishment. In vitro, Tec alleviated PA-induced cardiomyocyte lipotoxicity. Mechanistically, Tec directly bound EGFR at the E762/M793 sites and inhibited its aberrant activation. Inhibition of EGFR signaling suppressed the downstream EGFR-EGR2 axis, thereby upregulating Acot1 and improving myocardial lipid metabolic homeostasis. Cardiac-specific Acot1 knockdown or pharmacological activation of EGFR markedly attenuated Tec-mediated improvements in cardiac function, remodeling, and myocardial lipid metabolism. Tec ameliorates HFpEF through the EGFR-EGR2-Acot1 axis, highlighting a potential therapeutic strategy for HFpEF.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001087","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

Neutrophil extracellular traps in liver diseases: from molecular mechanisms to therapeutic interventions. 中性粒细胞胞外陷阱在肝脏疾病：从分子机制到治疗干预。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-17 DOI: 10.1038/s41401-026-01927-1

Wen-Xuan Liu, Miao Sun, Yu-Qian Xu, Na-Na Xu, Chao-Qun Chu, Rui Yang, Shuo Wang, Nan Li, Wei Wei, Wu-Yi Sun

{"title":"Neutrophil extracellular traps in liver diseases: from molecular mechanisms to therapeutic interventions.","authors":"Wen-Xuan Liu, Miao Sun, Yu-Qian Xu, Na-Na Xu, Chao-Qun Chu, Rui Yang, Shuo Wang, Nan Li, Wei Wei, Wu-Yi Sun","doi":"10.1038/s41401-026-01927-1","DOIUrl":"https://doi.org/10.1038/s41401-026-01927-1","url":null,"abstract":"Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors, including viral hepatitis, alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and hepatocellular carcinoma (HCC), etc. The characteristics of liver diseases are steatosis, hepatocyte ballooning, and immune cell infiltration. Among these immune cells, neutrophils are important immune cells in innate immunity. Under hepatic pathological conditions, neutrophils can produce neutrophil extracellular traps (NETs) under the stimulation of various factors, such as viral infections, metabolic disorders, toxic exposures, etc. Accumulating evidence has shown that NETs can interact with multiple signaling pathways and immune cells, regulate hepatic inflammatory responses, remodel the hepatic immune microenvironment, and promote the activation of hepatic stellate cells (HSCs). This review expounds the mechanism of NETs in various liver diseases, and the compounds or drugs that have been discovered or applied for the treatment of liver diseases by targeting NETs. This review enriches the pathogenesis of liver diseases and provides a theoretical basis and research directions for targeted therapeutic strategies.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987798","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

Small-molecule-induced neuron-specific hypoxia: recapitulating developmental angiogenesis for ischemic stroke therapy. 小分子诱导的神经元特异性缺氧：缺血性卒中治疗的重述发育性血管生成。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-17 DOI: 10.1038/s41401-026-01913-7

Xiao-Ying Wang, Zi-Yin Huang, Rui Han, Xin-Yu Li, Yan-Mei Song, Qi Wang, Fu-You Xu, Zi-Hui Zhu, Rong Cheng, Hao-Yu Wu, Yi-Qing Xia, Hai-Gang Ren, Xiao-Fan Pan, Guo-Dong Xiao, Jian Cheng, Jia Jia

{"title":"Small-molecule-induced neuron-specific hypoxia: recapitulating developmental angiogenesis for ischemic stroke therapy.","authors":"Xiao-Ying Wang, Zi-Yin Huang, Rui Han, Xin-Yu Li, Yan-Mei Song, Qi Wang, Fu-You Xu, Zi-Hui Zhu, Rong Cheng, Hao-Yu Wu, Yi-Qing Xia, Hai-Gang Ren, Xiao-Fan Pan, Guo-Dong Xiao, Jian Cheng, Jia Jia","doi":"10.1038/s41401-026-01913-7","DOIUrl":"https://doi.org/10.1038/s41401-026-01913-7","url":null,"abstract":"Hypoxia has therapeutic potential, but global hypoxia is toxic. Inducing safe, cell-specific hypoxia remains a clinically unmet need. We hypothesized that small-molecule-augmented oxygen consumption in adjacent cells induces neuron-specific hypoxia, representing a safe ischemic stroke strategy that mimics neural-directed developmental neovascularization. Using single-cell sequencing, a hypoxic probe, and knockout mice, we showed that ADT-OH (an active metabolite of a hepatoprotective drug) targeted sulfide-quinone oxidoreductase (SQR) to increase aerobic respiration in microglia/macrophages, thereby generating neuron-specific hypoxia after cerebral ischemia. Neuronal hypoxia promoted functional angiogenesis by specifically stabilizing hypoxia-inducible factor to upregulate the expression of neuron-derived vascular endothelial growth factor, supporting a neural-directed angiogenic mechanism. ADT-OH also restored the blood-brain barrier (BBB) via microglial/macrophage SQR. Notably, microglia/macrophage UCP2, the downstream mediator of SQR, was required for ADT-OH-induced BBB repair but not angiogenesis. Mechanistically, ADT-OH targeted UCP2 to increase Wnt/β-catenin signaling, which has been shown to mediate developmental BBB formation. In summary, one small molecule targeting SQR achieves therapeutic cell-specific hypoxia.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987828","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

Deeper delving Nav1.8 inhibitor Suzetrigine in chronic pain. 深入研究Nav1.8抑制剂舒三嗪在慢性疼痛中的作用。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-16 DOI: 10.1038/s41401-026-01939-x

Yu-Feng Xie

引用次数: 0

Lvguidingan inhibits Nav1.2 and epilepsy-associated SCN2A gain-of-function variants. Lvguidingan抑制Nav1.2和癫痫相关的SCN2A功能获得变异。

IF 10.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2026-09-15 DOI: 10.1038/s41401-026-01931-5

Long Wang, Xin-Yuan Hu, Zhi-Yong Gu, Hai-Yan Xu, Cheng-Hong Wu, Jun Chang, Zhao-Bing Gao

{"title":"Lvguidingan inhibits Nav1.2 and epilepsy-associated SCN2A gain-of-function variants.","authors":"Long Wang, Xin-Yuan Hu, Zhi-Yong Gu, Hai-Yan Xu, Cheng-Hong Wu, Jun Chang, Zhao-Bing Gao","doi":"10.1038/s41401-026-01931-5","DOIUrl":"https://doi.org/10.1038/s41401-026-01931-5","url":null,"abstract":"Voltage-gated sodium (Nav) channel Nav1.2, encoded by SCN2A, is a major determinant of neuronal excitability and an important contributor to epilepsy-associated hyperexcitability. However, small-molecule inhibitors with well-defined Nav1.2 pharmacology remain limited. Here, using an automated electrophysiological screening platform, we identified Lvguidingan (LV), an antiepileptic candidate that has entered phase II clinical evaluation in China, as a hit inhibitor of Nav1.2 and systematically characterized its pharmacological properties. Manual patch-clamp recordings showed that LV inhibited Nav1.2 and displayed differential inhibitory effects across other tested sodium channel subtypes. LV exhibited clear state- and use-dependent inhibition of Nav1.2 and shifted channel gating toward less available states. Molecular modeling and mutational analysis further identified key binding determinants underlying LV-mediated Nav1.2 inhibition. At the neuronal level, LV suppressed the firing of hippocampal neurons and reduced action potential amplitude. Importantly, LV also inhibited two epilepsy-associated SCN2A gain-of-function variants. Together, these results identify LV as a Nav1.2 inhibitor with defined biophysical and structural features and inhibitory activity against disease-associated SCN2A variants, providing new insight into the Nav1.2-related mechanism underlying the antiepileptic activity of LV.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975175","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