Acta Pharmacologica Sinica最新文献

{"title":"ALKBH5 deficiency suppresses hepatocarcinogenesis in mice via m⁶A-dependent STAT1 restoration.","authors":"Kai-Ting Wang, Shuai Yang, Zi-Han Zhao, Chun-Hua Rui, Si-Yun Shen, Dan Cao, Lin-Na Guo, Shan-Hua Tang, Lei Chen, Hong-Yang Wang, Xin-Yao Qiu","doi":"10.1038/s41401-025-01631-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01631-6","url":null,"abstract":"<p><p>RNA m⁶A methylation, as the most prevalent modification in mRNA, is a dynamic and reversible process primarily regulated by m⁶A methyltransferases (\"writers\"), m⁶A demethylases (\"erasers\"), and m⁶A recognition proteins (\"readers\"). It has been shown that N6-methyladenosine (m⁶A) plays a pivotal role in hepatocellular carcinoma (HCC). In this study we investigated the contribution of the m⁶A eraser AlkB homolog 5 (ALKBH5) to hepatocarcinogenesis, particularly during the early stages of liver cancer development. We found that liver-specific Alkbh5 conditional knockout (Alkbh5-cKO) profoundly suppressed DEN/CCl₄-induced HCC tumorigenesis and development in mice. We further showed that exogenous ALKBH5 expression drove the malignant transformation of immortal normal hepatocytes (HHL5, BNL), whereas ALKBH5 depletion in HCC cells restored hepatocyte-specific functions and suppressed malignancy. By conducting integrated MeRIP-seq/RNA-seq analyses, we identified STAT1 as a key target of ALKBH5-mediated m⁶A demethylation. ALKBH5 directly bound to STAT1 mRNA and reduced its m⁶A modification, thereby decreasing mRNA stability and suppressing STAT1 expression. Downregulated STAT1 inactivated the hepatocyte nuclear factor FOXA3, blocking hepatic differentiation and promoting malignancy. In 42 pairs of clinical HCC samples analyzed, STAT1 was negatively correlated with ALKBH5, and HCC patients with high ALKBH5 and low STAT1 expression exhibited worse clinical outcomes. We conclude that ALKBH5 is a critical oncogene in hepatocarcinogenesis. These results provide novel insights into the epigenetic regulation of hepatocarcinogenesis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938298","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":"DNMT inhibition epigenetically restores the cGAS-STING pathway and activates RIG-I/MDA5-MAVS to enhance antitumor immunity.","authors":"Yao Tu, Qing-Yun Zhu, Wen-Jun Huang, Sha Feng, Yu-Ling Tan, Lu-Lu Li, Xin-Tong Xie, Qin-Yuan Li, Shou-Hui Huang, Cheng-Zhou Mao, Bi-Zhu Chu, Yu-Yang Jiang","doi":"10.1038/s41401-025-01639-y","DOIUrl":"10.1038/s41401-025-01639-y","url":null,"abstract":"<p><p>The cGAS-STING cytosolic DNA-sensing pathway is a key mediator of the innate immune response and plays a crucial role in antitumor immunity. The expression of cGAS and STING is often suppressed in tumor cells, and reduced expression is associated with poor prognosis and inferior response to immunotherapy. In this study we systematically investigated the expression pattern of cGAS-STING pathway in tumors and its correlation with immunotherapy response. We showed that the expression of cGAS and STING was significantly decreased or undetectable in most breast cancer and murine tumor cell lines, while high cGAS and STING expression was associated with increased T cell infiltration, elevated PD-L1 and PD-1 levels, improved immunotherapy response and prolonged survival. In cGAS-STING-deficient MDA-MB-453 cells, DNMT inhibitor decitabine (DAC, 0.05-1 μM) dose-dependently restored the impaired pathway by reversing DNA methylation-mediated silencing. Furthermore, DAC combined with a chemotherapeutic agent cisplatin significantly enhanced the antitumor effect in MDA-MB-453 and MDA-MB-231 cells by activating the cGAS-STING pathway through cytoplasmic DNA accumulation. In addition, DNMT inhibition elevated intracellular dsRNA levels and activated the RIG-I/MDA5-MAVS pathway. These results suggest that DNMT inhibitors can epigenetically reprogram the cGAS-STING pathway, activate the RIG-I/MDA5-MAVS pathway, and in combination with chemotherapeutic agents, synergistically promote antitumor immunity. Together, this study identifies cGAS-STING as a potential predictor of immunotherapy response and highlights a novel therapeutic strategy for restoring innate immune function in cancer. Loss of cGAS-STING signaling in tumors impairs antitumor immunity and correlates with poor immunotherapy response. DNMT inhibition restores cGAS-STING pathway and concurrently activates the RIG-I/MDA5-MAVS signaling, synergistically enhancing immune infiltration and antitumor efficacy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881815","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":"Novel anti-HER2 nanobody-drug conjugates with enhanced penetration of solid tumor and BBB, reduced systemic exposure and superior antitumor efficacy.","authors":"Yue Wang, Liang Liu, Qi-Yu Yang, Ker Yu","doi":"10.1038/s41401-025-01634-3","DOIUrl":"10.1038/s41401-025-01634-3","url":null,"abstract":"<p><p>Antibody-drug conjugate (ADC) represents a promising paradigm for tumor-targeted delivery of chemotherapy. Trastuzumab deruxtecan (T-Dxd/DS-8201), a second-generation HER2-ADC, has significantly improved treatment outcomes for breast cancer patients. But due to the large molecular weight, the performance of ADC is still limited by lower tumor penetration, insufficient BBB permeability, and prolonged systemic exposure to normal tissues. In this study, we generated novel anti-HER2 nanobodies (VHH2, VHH3) that exhibited outstanding target affinity and tumor inhibition. After i.v. injection, VHH3-Fc fusion distributed 4 to 5-fold higher in subcutaneous tumor and intracranial tumor compared with trastuzumab. VHH3-Fc and VHH3-ABD were also more penetrant in an in vitro BBB permeability assay. Site-specific conjugation of VHH3-Fc or VHH3-ABD fusions with anti-microtubule MMAE or anti-topoisomerase-1 Dxd payload produced nanobody-drug conjugates (NDCs) with highly potent and durable antitumor efficacy. When evaluated on the same linker-payload (GGFG-Dxd) dosages, VHH3-Fc-Dxd (DAR3.9) outperformed T-Dxd (DAR8) in both the subcutaneous and intracranial tumor models. Moreover, IHC staining and RNA-seq analysis of the treated tumor tissues revealed the involvement of the cGAS-STING-IFNs pathway in mediating the drug activity. Gene expression and protein function were more profoundly modulated by VHH3-Fc-Dxd than T-Dxd. Unlike the higher tumor distribution, the mouse serum PK study revealed a faster clearance (T_1/2), reduced exposure (AUC), and higher volume distribution (Vz) for VHH3-Fc-Dxd relative to T-Dxd. Our results provide an example for the next generation HER2-NDC with substantially differentiated pharmacokinetics and pharmacodynamics profiles that will further benefit treatment outcomes and therapeutic windows.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870725","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":"Inhibition of Setd7 protects against cardiomyocyte hypertrophy via inhibiting lipid oxidation.","authors":"Hai-Bi Su, Jing-Huan Wang, Yu-Yu Zhang, Jie Xu, Jia-Yao Liu, Yu-Hui Li, Chen-Xi Xiao, Cai-Yun Wang, Jun Chang, Xin-Hua Liu","doi":"10.1038/s41401-025-01626-3","DOIUrl":"https://doi.org/10.1038/s41401-025-01626-3","url":null,"abstract":"<p><p>Myocardial hypertrophy is one of the most prominent features of heart failure. SET domain-containing protein 7 (Setd7), a catalytic enzyme responsible for histone H3K4 methylation, has been implicated in various cardiac diseases. In this study we investigated whether Setd7 contributed to the development of cardiac hypertrophy. Male mice were subjected to a hypobaric hypoxic environment for 8 weeks; neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia for 6 h. We showed that hypoxic stimulation significantly upregulated the expression levels of Setd7 along with the expression of hypertrophic markers ANP and BNP in NRCMs. By conducting loss- and gain-of-function assays, we demonstrated that Setd7 modulated the hypertrophic and inflammatory markers in hypoxic cardiomyocytes. We further revealed that Setd7-mediated activation of E2F1 (E2 promoter binding factor 1) triggered the expression of E3 ubiquitin protein ligases WWP2, which catalyzed the ubiquitination and degradation of glutathione peroxidase 4 (GPx4), a critical lipid peroxide-reducing enzyme. This degradation drove extensive lipid peroxidation, thereby exacerbating pathological cardiac hypertrophy. Notably, GPx4 inhibition by ras-selective lethal small molecule 3 (RSL3) abolished the antihypertrophic effects of Setd7 knockdown in cardiomyocytes, underscoring the pivotal role of lipid peroxidation in Setd7-mediated hypertrophic responses. In summary, Setd7 promotes hypoxia-induced cardiac hypertrophy through the Setd7-E2F1-WWP2-GPx4 signaling pathway, suggesting that targeting Setd7 is a promising therapeutic strategy to alleviate hypoxia-induced myocardial hypertrophy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833690","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":"Novel IL13RA2-targeted immunocytokines exhibit superior antitumor activities.","authors":"Qing-Qing Jing, Jing Wen, Jian-Xia Ou, Yan-Ting He, Yu-Ting Zhang, Gul E Rana, Qi Wang, Gui-Feng Wang, Chun-He Wang","doi":"10.1038/s41401-025-01611-w","DOIUrl":"https://doi.org/10.1038/s41401-025-01611-w","url":null,"abstract":"<p><p>Th1-type cytokines such as interleukin-2 (IL-2) and interleukin-12 (IL-12) are known for their potent antitumor activities, but their clinical application has been hindered by significant side effects. Immunocytokines (ICs) that combine cytokines with antibodies have shown favorable therapeutic and safety outcomes in clinical trials. In this study we first investigated the expression patterns and prognostic significance of IL13RA2 across various cancer types through a comprehensive analysis of the TIMER2 and TCGA datasets. Subsequently, we generated 52B8, a neutralizing antibody against interleukin-13 receptor alpha 2 (IL13RA2) as well as three ICs incorporating interleukin-2 (IL-2), interleukin-12 (IL-12), or both, designed as 52B8-IL2, 52B8-IL12 and 52B8-IL2/12, respectively. The ICs exhibited potent and dose-dependent anticancer activity both in vitro and in MC38-hIL13RA2-GFP and A375 tumor xenograft models in vivo. In addition, they exhibited significantly reduced side effects through targeted cytokine delivery as well as enhanced immune cell infiltration into tumors. Collectively, our results suggest that IL13RA2-targeting ICs represent a promising therapeutic strategy for the treatment of IL13RA2-positive tumors.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833692","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":"Identification of small-molecule inhibitors for GluN1/GluN3A NMDA receptors via a multiscale CNN-based prediction model.","authors":"Li Han, Yue Zeng, Zhi-Yan Qu, Sui Fang, Hai-Ying Wang, Ya-Shuo Dong, Xiang-Ming Zeng, Tong-Yan Zhang, Ze-Bin Yu, Ling Kang, Zhao-Bing Gao, Quan Guo","doi":"10.1038/s41401-025-01630-7","DOIUrl":"https://doi.org/10.1038/s41401-025-01630-7","url":null,"abstract":"<p><p>N-methyl-D-aspartate receptors (NMDARs) are critical mediators of excitatory neurotransmission and are composed of seven subunits (GluN1, GluN2A-D, and GluN3A-B) that form diverse receptor subtypes. While GluN1/GluN2 subtypes have been extensively characterized and have led to approved therapeutics, the GluN1/GluN3A subtype remains underexplored despite emerging evidence of its involvement in neuropsychiatric disorders. Efficient identification of modulators requires accurate prediction of drug-target affinity (DTA), particularly for challenging targets such as GluN1/GluN3A. In this study, we applied the ImageDTA model, which is a multiscale 2D convolutional neural network (CNN), to virtually screen 18 million small molecules for GluN1/GluN3A inhibitors. This artificial intelligence (AI)-driven approach prioritized 12 compounds, three of which demonstrated potent inhibitory activity (IC₅₀ < 30 µM) in experimental validation. The most potent hit, with an IC₅₀ of 4.16 ± 0.65 µM, revealed a novel structural scaffold, thus highlighting the potential of AI in accelerating drug discovery for underexplored receptor subtypes. These findings establish a robust framework for advancing GluN1/GluN3A-targeted therapeutics.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833689","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":"Neuroglia and immune cells play different roles in neuroinflammation and neuroimmune response in post-stroke neural injury and repair.","authors":"Hui Guo, Wen-Cao Liu, Yan-Yun Sun, Xin-Chun Jin, Pan-Pan Geng","doi":"10.1038/s41401-025-01640-5","DOIUrl":"10.1038/s41401-025-01640-5","url":null,"abstract":"<p><p>Neuroinflammation and immune responses mediated by glial cells and immune cells play dual roles in the neural injury and repair of ischemic stroke (IS): glial cells and immune cells primarily have a detrimental role in the acute phase of IS, while they mainly serve a reparative function in the chronic phase. Thus, suppressing neuroinflammation and immune responses driven by glial and immune cells represents a major strategy in the treatment of IS. In this review, we provide an overview of the molecular mechanisms of neuroinflammation and immune responses mediated by glial cells and immune cells at different stages after IS and highlight the roles of different glial cells and immune cells in post-IS neural injury and repair. We also summarize the relevant molecular targets and clinical application challenges for reducing neuroinflammation and immune responses to promote IS repair. Current evidence supports that PD-1/PD-L1, DAPK1, HDAC3-p65-cGAS-STING could be the targets. In addition, we discuss some treatment strategies for reducing neuroinflammation and immune responses such as traditional Chinese medicine (TCM) and natural product therapy, stem cell-based therapy and biomaterials, as well as current clinical trial progress and prospects.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833691","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":"NADPH acts as an endogenous P2X7 receptor modulator to gate neuroinflammatory responses of microglia.","authors":"Yu-Jie Mou, Feng-Min Li, Jun-Tong Lou, Hai-Yue Tu, Yi Zhu, Rui Sheng, Zhong-Ling Zhang, Yu-Zheng Zhao, Fu-Hai Ji, Jun-Chao Wu, Zheng-Hong Qin","doi":"10.1038/s41401-025-01638-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01638-z","url":null,"abstract":"<p><p>Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is an important coenzyme involved in cellular biosynthetic and redox metabolism. It has been recognized for its role in regulating neuroinflammation through coordinating redox reactions. Whether there are new actions other than redox regulation remain unclear. In this study we investigated a novel mechanism by which NADPH regulated microglia-mediated neuroinflammation. We showed that NADPH application significantly alleviated NLRP3 inflammasome activation in microglia and exerted neuroprotective effects both in vitro and in vivo neuroinflammation models. With P2X7R knockdown microglial cells and P2X7R^cKO mice, we demonstrated that P2X7R was a crucial mediator of the anti-inflammatory effects for the supplemented NADPH. We conducted whole-cell recording from murine microglial cell line BV2 cells, and found that application of ATP (1 mM) elicited an inward current, which was reduced by co-application of P2X7R antagonist A-438079 (20 μM) or NADPH (1 mM). By performing a drug affinity responsive targets stability (DARTS) assay, we revealed that NADPH (not NADP⁺ or NADH), like the P2X7R agonist ATP, bound to the extracellular domain of P2X7R, leading to the suppression of ATP-induced P2X7R activation. Our research provides the first evidence of NADPH as an endogenous inhibitor of P2X7R in modulation of microglia-mediated neuroinflammation. This study expands the biological functions of NADPH and offers a novel target for NADPH-based therapies in neuroimmune-related diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820331","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":"Dendritic cell-liposome conjugates reverse immunosuppressive tumor microenvironment for inhibiting colitis-associated colorectal cancer.","authors":"Wen-Zhe Yi, Xin-di Qian, Xiao-Xuan Xu, Rong Pu, Dan Yan, Zhi-Wen Zhao, Ya-Ping Li, Dang-Ge Wang","doi":"10.1038/s41401-025-01614-7","DOIUrl":"https://doi.org/10.1038/s41401-025-01614-7","url":null,"abstract":"<p><p>The progression of colitis-associated cancer (CAC) is strongly associated with bone marrow-derived immunosuppressive cells (MDSCs). Although CAC could be suppressed by inducing MDSCs apoptosis, the immunosuppressive tumor microenvironment (TME) maintains immune homeostasis by upregulating M2-type tumor-associated macrophages (TAMs), thus leading to adaptive immune tolerance. Herein, we develop a dendritic cell (DC)-liposome conjugate to reverse immunosuppressive TME, showing remarkable efficiency against colorectal cancer. The DC-liposome conjugate is fabricated by conjugating resolvin E1-loaded liposomes with Fas ligand-transfected DCs, which eliminates tumor-infiltrated Fas⁺ MDSCs and enhances TAM phagocytosis in tumors. It shows significant therapeutic effects in preclinical CAC models and alleviates severe colitis when combined with immune checkpoint inhibitors. This study provides a feasible and customized cell-drug conjugate to overcome immunosuppressive TME for enhancing CAC immunotherapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803244","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":"Galangin, a novel Kv7 potassium channel opener, exerts potent antinociceptive effects in multiple chronic pain mouse models.","authors":"Bo Yang, Hui Liu, Wen-Jing Zhao, Jia-Rui Ma, Zi-Shuo Kang, Yu-Jie Zhang, Yu-Lin Gu, Xiao-Ke Li, Zeng-Wei Mao, Rui-Feng Cao, Ya-Ling Wang, Han Li, Fan Zhang","doi":"10.1038/s41401-025-01627-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01627-2","url":null,"abstract":"<p><p>The activation of voltage-gated potassium Kv7/M channels is an attractive therapeutic strategy for chronic pain. Galangin, the principal active component of the medicinal herb Alpinia officinarum Hance, has exhibited analgesic effects in mice. In this study, we investigated the antinociceptive effects of galangin in the treatment of various types of chronic pain and the underlying mechanisms. Using whole-cell recordings of CHO cells expressing Kv7.2/Kv7.3 channels, we showed that galangin enhanced Kv7.2/Kv7.3 currents in a concentration-dependent manner, with an EC₅₀ value of 8.8 ± 1.6 μM, and shifted the voltage-dependent activation curve of the channels toward depolarization. We demonstrated that galangin selectively and potently activated the Kv7.2, Kv7.4, and Kv7.5 channels while reducing the Kv7.1 current and exerting no effect on the Kv7.3 current. Notably, galangin no longer increased the current amplitude and slightly shifted the voltage-dependent activation of the Kv7.2 (E322A) mutant, suggesting that Glu-322 in Kv7.2 is important for galangin activation of the channels. Moreover, we showed that galangin (100 μM) significantly enhanced the M-current and consequently reduced the excitability of DRG neurons in SNI mice. In multiple chronic pain mouse models, the administration of galangin (15 mg/kg, i.p.) significantly increased the threshold for mechanical stimuli and the withdrawal latency to thermal stimuli, which were reversed by the Kv7/M channel blocker XE991. Taken together, the results of this study demonstrated that galangin exerts its antinociceptive effects mainly through the activation of Kv7/M channels, representing a novel approach for treating neuronal excitatory diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797932","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}