Acta Pharmacologica Sinica最新文献

{"title":"Neddylation as a molecular integrator of metabolic dysfunction and endothelial dysfunction in type 2 diabetes.","authors":"Zhongjian Cheng, Chris Wittmann, Raj Kishore","doi":"10.1038/s41401-026-01910-w","DOIUrl":"10.1038/s41401-026-01910-w","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2D) is a major global health challenge associated with a high burden of cardiovascular and microvascular complications. Endothelial dysfunction is a hallmark of T2D and represents a critical link between metabolic abnormalities and vascular disease. Chronic hyperglycemia, insulin resistance, obesity-associated inflammation, oxidative stress, and mitochondrial dysfunction disrupt endothelial homeostasis, resulting in impaired nitric oxide bioavailability, vascular inflammation, endothelial senescence, barrier dysfunction, and defective vascular repair. However, the molecular mechanisms integrating metabolic stress with endothelial injury in T2D remain incompletely understood. Neddylation is a reversible ubiquitin-like post-translational modification mediated by neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Through activation of Cullin-RING E3 ubiquitin ligases and modification of non-cullin substrates, neddylation regulates protein turnover, signal transduction, metabolism, inflammation, oxidative stress responses, and mitochondrial homeostasis. Emerging evidence suggests that dysregulated neddylation contributes to several metabolic abnormalities implicated in endothelial dysfunction, including insulin resistance, obesity-associated metabolic dysfunction, oxidative stress, and mitochondrial dysfunction. In diabetic retinopathy, excessive cullin neddylation promotes degradation of protective factors such as nuclear factor erythroid 2-related factor 2 (NRF2) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), thereby enhancing oxidative stress, inflammation, vascular leakage, and pathological angiogenesis. Conversely, physiological neddylation appears necessary for endothelial homeostasis through regulation of endothelial barrier integrity, angiogenesis, and stabilization of vascular endothelial growth factor receptor 2 (VEGFR2). Although direct evidence remains largely limited to retinal endothelial cells and diabetic retinopathy models, current findings support the hypothesis that dysregulated neddylation may act as an important molecular link between metabolic dysfunction and endothelial injury in diabetes. Pharmacological modulation of the neddylation pathway, including inhibition of the NEDD8-activating enzyme with MLN4924 (pevonedistat), improves metabolic homeostasis, suppresses inflammatory signaling, enhances antioxidant defenses, and attenuates vascular injury in preclinical studies. In this review, we summarize current advances in neddylation biology, discuss emerging evidence linking dysregulated neddylation to diabetes-associated endothelial dysfunction, highlight critical knowledge gaps, and evaluate the opportunities and challenges of targeting the neddylation pathway for the prevention and treatment of diabetic vascular complications.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial TLR7 contributes to traumatic brain injury-induced neuroinflammation in mice.","authors":"Yi-Teng Du, Xiao-Li Ma, Shu-Hui Gao, Yan-Xia Wang, Yan Liu, Xue-Mei Feng, Chen Fan, Hong-Zhuan Chen, Ming-Ke Song","doi":"10.1038/s41401-026-01915-5","DOIUrl":"https://doi.org/10.1038/s41401-026-01915-5","url":null,"abstract":"<p><p>Neuroinflammation driven by activated microglia is an important component of secondary injury after traumatic brain injury (TBI), but the underlying molecular mechanisms remain incompletely understood. Here, we investigated the role of microglial Toll-like receptor 7 (TLR7) in TBI-induced neuroinflammation and evaluated the therapeutic effect of the TLR7-targeting compound Enpatoran (M5049). Analysis of public single-cell transcriptomic datasets showed that TLR7 is preferentially expressed in microglia among resident brain cells. In the controlled cortical impact (CCI) mouse TBI model, TBI increased TLR7 expression in microglia and elevated the abundance of cleaved-TLR7 in the peri-contusional cortex. Knockdown of the asparaginyl endopeptidase (AEP) attenuated TLR7 cleavage and downstream signaling in cultured microglia. Deletion of AEP decreased cleaved-TLR7 and inflammatory marker expression in TBI mice, indicating an AEP-mediated proteolytic processing of TLR7 and suggesting TLR7's involvement in TBI inflammation. Global TLR7 deletion in mice failed to reduce TBI-induced inflammation and was accompanied by marked TLR8 upregulation. In contrast, inducible microglia-specific TLR7 deletion in mice attenuated CD86, TNF-α, and IL-1β expression without a pronounced TLR8 upregulation. The TLR7 inhibitor M5049 suppressed TLR7 agonist-induced inflammation in cultured microglia without inhibiting mouse TLR8. In TBI mice, treatment with M5049 at 0.1, 0.3, and 3 mg/kg all significantly reduced TBI-induced IL-1β and IL-6 mRNA expression. Pharmacological tests further showed that M5049 is effective in suppressing TBI-induced microglial activation and inflammatory cytokine secretion in wild-type mice but lost this efficacy in TLR7 knockout mice. Therefore, M5049's anti-inflammatory action relies on the presence of TLR7. Additionally, M5049 was not able to rescue glutamate- and H₂O₂-induced cell death in HT22 mouse hippocampus neuronal cells, or broadly suppress the examined peripheral immune transcriptional program. These findings identify microglial TLR7 as an important player in TBI-induced neuroinflammation and support a predominantly TLR7-dependent anti-inflammatory effect of M5049.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811722","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":"Berberrubine alleviates PCS-induced tubular injury via HNRNPF/NR4A1/ER stress axis.","authors":"Ying Liu, Yong-Song Wang, Shu-Fan Jin, Meng-Ting Yuan, Shi-Qing Zhao, Jie Zhang, Wen-Yuan Liu, Feng Feng, Jian Xu","doi":"10.1038/s41401-026-01911-9","DOIUrl":"https://doi.org/10.1038/s41401-026-01911-9","url":null,"abstract":"<p><p>The key uremic toxin p-cresyl sulfate (PCS) has been shown to induce renal tubule injury-mediated chronic kidney disease via endoplasmic reticulum stress (ERS). Berberine offers renoprotective benefits and attenuates ERS-driven apoptosis. Owing to the low oral bioavailability of berberine, its primary metabolite, berberrubine (BRB), here considered a direct bioactive-agent responsible for its effects. However, the protective effects of BRB against nephritic damage and its regulatory function involving ERS or underlying molecular targets remain poorly understood. In this work, biochemical, cellular assays and animal studies revealed that BRB alleviates PCS-induced renal dysfunction, pathological damage, ERS and apoptosis. Additionally, transcriptomics, biochemical and cellular assays revealed that BRB effectively inhibited the PCS-mediated phosphorylation and nuclear translocation of NR4A1, which in turn suppressed the GRP78/IRE1α/XBP1s/CHOP signaling pathway. Mechanistically, DARTS, CETSA, SPR and mutant plasmids identified HNRNPF as the functional target of BRB, with key binding sites TYR306 and ASN313, further revealing its role as a critical regulator of the NR4A1/GRP78/IRE1α/XBP1s/CHOP signaling pathway in HNRNPF-knockdown/overexpressing HK-2 cells and AAV9-saCAS9-sgRNA knockdown C57BL/6 mice. Our findings reveal a previously unrecognized HNRNPF/NR4A1/ERS pathway in which BRB targets HNRNPF as a newly identified small-molecule ligand, and these results offer valuable insights into the potential targeting of HNRNPF for the treatment of tubule lesions.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811735","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 CYBA inhibits hepatic metastasis of pancreatic cancer through AKT/MLC2 pathway.","authors":"Hao-Jie Du, Wen Fang, Qin-Chang Zhang, Na-Na Chen, Feng-Lin Zhang, Jian-Gang Zhao, Ji-Hong Lv, Kong Mingyui Anthony, Hao Chen, Jian-Jun Zou, Yang Sun, Hai-Bo Cheng","doi":"10.1038/s41401-026-01880-z","DOIUrl":"https://doi.org/10.1038/s41401-026-01880-z","url":null,"abstract":"<p><p>Pancreatic cancer is known as the \"king of cancers\", mainly due to its aggressive metastatic potential and significant heterogeneity. The liver represents the most frequent site of distant metastasis in pancreatic ductal adenocarcinoma (PDAC). Currently, effective treatment options remain critically limited for patients diagnosed with PDAC-derived hepatic metastases. In our research, we integrated single-cell transcriptomic data from multiple samples to delve into the heterogeneity of epithelial cells. We identified a subtype of malignant metastatic epithelial cells and identified CYBA, which encodes the p22^phox protein, as a key molecular target promoting hepatic metastasis in PDAC. Through experimental validation, we confirmed that p22^phox was highly expressed in pancreatic cancer samples with hepatic metastasis, and its knockdown inhibited the migration of pancreatic cancer cells and metastasis to the liver. Mechanistically, p22^phox activated the PI3K-AKT signaling pathway and increased MLC2 phosphorylation, facilitating the polymerization of motor proteins in pancreatic cancer cells and promoting tumor metastasis. NOX inhibitors were found to suppress PI3K-AKT and p-MLC2 pathways, as well as inhibit the migration of pancreatic cancer cells and metastasis to the liver. Therefore, targeting the activity of p22^phox in pancreatic cancer may emerge as an effective therapeutic strategy for treating hepatic metastasis in PDAC patients.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786744","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":"AKT (Ser473) suppression mediates ceritinib cardiotoxicity through autophagic flux impairment and mitochondrial injury.","authors":"Feng Jiang, Huang-Xi Fu, Lan Wang, Ze-Zheng Pan, Yan-Qi Jiang, Ning Liu, Xue-Qin Chen, Zi-Zheng Gao, Wen-Tong Wu, Hao Yan, Xiao-Chun Yang, Bo Yang, Qiao-Jun He, Pei-Hua Luo, Zhi-Fei Xu","doi":"10.1038/s41401-026-01917-3","DOIUrl":"https://doi.org/10.1038/s41401-026-01917-3","url":null,"abstract":"<p><p>Ceritinib, an anaplastic lymphoma kinase (ALK) inhibitor, is associated with cardiovascular adverse events, yet the mechanisms remain incompletely understood. Here, we show that ceritinib impairs left ventricular systolic function in mice and induces cardiomyocyte apoptosis, and identify AKT (Ser473) suppression as a key initiating event. Loss of AKT activity is paralleled by reduced phosphorylation of mTOR (Ser2448) and ULK1 (Ser757), consistent with enhanced autophagy initiation. Concurrently, loss of inhibitory GSK3β (Ser9) phosphorylation correlates with impaired lysosomal function, reflected by disrupted cathepsin D maturation and reduced lysosomal acidification. This mismatch between enhanced autophagy initiation and impaired lysosomal clearance impairs autophagic flux despite preserved autophagosome-lysosome fusion, and causes mitochondrial damage, evidenced by reduced TOMM20 and HSP60 expression and membrane potential loss. Transcriptomic and functional analyses identify AKT2 as a particularly vulnerable isoform in this network. Metformin co-treatment preserves cardiac function and attenuates apoptosis. Mechanistically, metformin increases AMPK (Thr172) phosphorylation and reduces TFEB (Ser122) phosphorylation, restores CTSD maturation, and decreases LC3-II accumulation. These protective effects occur without reversing the suppressed AKT (Ser473) or GSK3β (Ser9) phosphorylation. Together, these findings establish that AKT suppression drives ceritinib cardiotoxicity through autophagic flux impairment and mitochondrial injury, and position AMPK-driven, TFEB-associated lysosomal restoration as a mechanism-based cardioprotective strategy independent of AKT recovery.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786769","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":"RNF6 activates the AKT/mTOR signaling pathway by inhibiting PTEN via K27-linked polyubiquitination in myeloma.","authors":"Yue-Ya Zhong, Li-Huan Zhang, Zi-Yang Liu, Na Tao, Zi-Fu Fan, Ke Li, Hong-Xia Zhang, Yao-Li Cui, Ya-Li Wang, Xin-Liang Mao","doi":"10.1038/s41401-026-01900-y","DOIUrl":"https://doi.org/10.1038/s41401-026-01900-y","url":null,"abstract":"<p><p>As the second most hematological malignancy, multiple myeloma (MM) is closely associated with dysregulated AKT/mTOR signaling. However, the underlying mechanism remains unclear. In the present study, we find the AKT/mTOR signaling pathway is activated by the ring finger protein RNF6. Acting as a ubiquitin ligase, RNF6 binds to and mediates PTEN polyubiquitination, altering its stability. Further investigations reveal that RNF6 specifically induces K27-linked ubiquitination of PTEN. RNF6 also prevents PTEN from translocalization to the plasma membrane, thereby inhibiting its phosphatase activity. Consistent with this finding, RNF6 promotes the production of PI(3,4,5)P3, and when PTEN is depleted, RNF6 fails to activate AKT/mTOR signaling. Moreover, we find USP39 binds to PTEN and abolishes K27-linked polyubiquitination mediated by RNF6. Furthermore, USP39 suppresses AKT/mTOR signaling transduction activated by RNF6. In addition, RNF6 is found to promote glycolysis in myeloma cells, but this effect is inhibited by USP39. Lastly, we discovered that oleandrin, a natural product, induces K48-linked polyubiquitination of RNF6 and subsequent degradation, thereby suppressing PTEN with K27-linked polyubiquitination and the AKT/mTOR signaling pathway. In conclusion, the study identifies RNF6 and USP39 as novel ubiquitin ligases or deubiquitinases responsible for K27-linked polyubiquitination of PTEN and as novel modulators of the AKT/mTOR pathway. Targeting the RNF6/PTEN/AKT/mTOR signaling axis might represent a novel therapeutic strategy for myeloma treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786772","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":"A prelimbic cortex-lateral hypothalamus circuit regulates acquisition of alprazolam-induced conditioned place preference in male mice.","authors":"Zhi-Peng Song, Nian-Ci Li, Rui Song, Cheng Zheng, Cun Wang, Fei-Zhi Liao, Su-Su Tang, Dan-Hua Yuan, Hao Hong, Zhi-Gang Chen, Yan Long","doi":"10.1038/s41401-026-01909-3","DOIUrl":"https://doi.org/10.1038/s41401-026-01909-3","url":null,"abstract":"<p><p>Alprazolam (Alp), a high-potency benzodiazepine, poses a significant risk of abuse and addiction, yet the precise mechanisms underlying Alp-associated reward memory remain poorly defined. Here, we first established that administration of Alp at 10 mg/kg reliably induces conditioned place preference (CPP) in male mice. Our results indicated that prelimbic cortex (PrL) CaMKⅡα neurons were hyperactive in Alp-trained mice. Chemogenetic manipulation of the activity of PrL CaMKⅡα neurons bidirectionally regulated acquisition of Alp-induced CPP. Furthermore, virus tracing indicated a strong PrL CaMKⅡα neuron projection to lateral hypothalamus (LH). Suppression of the PrL-LH circuit significantly decreased acquisition of Alp-induced CPP, while potentiation of this circuit facilitated Alp-induced CPP. Activation of PrL^CaMKⅡα-LH circuit failed to produce real-time place preference. In summary, our results indicate that PrL glutamatergic neurons and the PrL-LH circuit regulate Alp-induced reward memory formation, providing a foundation for elucidating the neural mechanisms underlying Alp addiction.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786763","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":"SRPK3 exacerbates cardiac ischemia/reperfusion injury by regulating KLF3-mTOR/P70 S6K-mediated autophagy.","authors":"Yun Xing, Sai-Yang Xie, Nan Zhao, Chao-Jun Sun, Gao-Yuan Liang, Xian-Xian Meng, Wei Deng, Qi-Zhu Tang","doi":"10.1038/s41401-026-01906-6","DOIUrl":"https://doi.org/10.1038/s41401-026-01906-6","url":null,"abstract":"<p><p>Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of cardiac dysfunction and mortality worldwide. Serine/arginine-Rich Protein Kinase 3 (SRPK3) is highly expressed in cardiac muscle, yet its specific pathological role in I/R injury has not been fully characterized. In this study, we utilized cardiac-specific knockout mouse models and cardiomyocyte hypoxia/reoxygenation assays to investigate the function of SRPK3. Our results demonstrated that SRPK3 deficiency significantly preserved cardiac function, reduced infarct size, and attenuated apoptosis and oxidative stress. Conversely, SRPK3 overexpression exacerbated these pathological phenotypes. Mechanistically, by integrating transcriptomics, phosphoproteomics, and site-directed mutagenesis, we revealed that SRPK3 directly phosphorylates the Transcription Factor KLF3 at the Ser71 residue. This phosphorylation event disrupts KLF3-mediated transcriptional activation of mTOR, thereby suppressing the mTOR/P70 S6K signaling axis. Consequently, this inhibition unleashes an excessive, maladaptive autophagic flux that transitions from a homeostatic mechanism to a lethal process, further aggravating myocardial injury. Collectively, we systematically elucidate that SRPK3 acts as a detrimental regulator in myocardial I/R injury by inducing lethal autophagy via the KLF3-mTOR axis. These findings identify the SRPK3-KLF3 interaction as a critical molecular switch and offer a promising therapeutic target for managing ischemic heart disease. This figure systematically delineates the mechanistic role of SRPK3 in myocardial ischemia/reperfusion injury. Acting as a critical regulatory factor, SRPK3 phosphorylates KLF3 at the Ser71 residue and concomitantly suppresses the mTOR signaling pathway, thereby inducing excessive pathological autophagy. This dysregulated autophagic flux, characterized by increased autophagosome formation, loses its cytoprotective function and instead exacerbates cardiomyocyte apoptosis and oxidative stress, ultimately leading to deterioration of cardiac function.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786833","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":"Neuromodulatory roles of the sigma-1 receptor in behavior and drug sensitization during development.","authors":"Qian Yang, Jia-Hui Xiao, Jia-Yuan Li, Zhe-Xiang Yu, Ping-Ping Qin, Yi Zhu, Na Ye, Xin-Hao Li, Shi-Lei Zhang, Yu Sun, Qi-Fei Cong, Xue-Chu Zhen, Guang-Ying Li","doi":"10.1038/s41401-026-01903-9","DOIUrl":"https://doi.org/10.1038/s41401-026-01903-9","url":null,"abstract":"<p><p>The sigma-1 receptor (S1R), which functions as both a receptor and molecular chaperone, plays pivotal roles in various biological processes. Its widespread involvement in central neurotransmitter regulation positions S1R as a potential target for neuropsychiatric disorders, including drug addiction, schizophrenia and neurodegenerative diseases. However, the mechanisms underlying the heightened susceptibility of individuals with S1R deficiency to neurological diseases remain elusive. This study investigated the neuromodulatory role of S1R in pyramidal neurons in the barrel field of the primary somatosensory cortex (S1BF) and the medial prefrontal cortex (mPFC) in young mice across three developmental time points (postnatal days 14, 21, and 28). By employing whole-cell recordings, we revealed distinct effects of S1R on sEPSCs, sIPSCs, and the excitatory/inhibitory (E/I) balance during the critical period. Specifically, S1R^-/- mice at P21 had substantially reduced sIPSC frequency, resulting in a noteworthy increase in the excitatory/inhibitory (E/I) ratio. In contrast, at P14 and P28, the sEPSCs and sIPSCs of the S1R^-/- mice were not affected. Adult knockout mice exhibited drug-induced behavioral sensitization to methamphetamine (METH). Mechanistic studies revealed that the administration of METH caused an E/I imbalance of pyramidal neurons in the mPFC and a decrease in the density of dendritic spines, which was accompanied by a decrease in the protein levels of brain-derived neurotrophic factor (BDNF). SOMCL-668, an allosteric modulator of S1R, attenuated METH-induced behavioral sensitization in a dose-dependent manner through attenuating excitatory synaptic transmission and modulating the p-CREB/CREB ratio. Collectively, our results underscore the developmental dynamics of S1R-mediated regulation of synaptic plasticity, offering significant implications for treatment strategies targeting S1R deficiency and disruptions in E/I balance. Finally, our findings demonstrated that S1R is involved in METH-induced behavioral sensitization and that SOMCL-668 could be a potential therapeutic agent for drug addiction.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786822","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":"Direct β-arrestin engagement by the non-canonical WNT receptor FZD6 via a shallow binding pocket.","authors":"Zhi-Bin Zhang, Xi Lin, Meng-Rao Li, Yu-Rui Pan, Qing Kang, Fei Xu, Xiang-Jia Zhu","doi":"10.1038/s41401-026-01902-w","DOIUrl":"https://doi.org/10.1038/s41401-026-01902-w","url":null,"abstract":"<p><p>As primary WNT receptors, Frizzled (FZD) receptors behave as nonclassical GPCRs; however, their engagement with downstream transducers is largely unknown. Previous studies have suggested that β-arrestin recruitment to FZD receptors depends on its interaction with Dishevelled (DVL) and that this process regulates both canonical and non-canonical pathways. Here, we reveal that FZD6, which mainly mediates non-canonical WNT signalling, directly binds to β-arrestin 1 (βarr1) and report the cryo-EM structure of the FZD6-βarr1 complex, which revealed a unique shallow pocket in FZD6 for βarr1 engagement and identified arrestin-specific motifs that are distinct from those observed in previously reported FZD receptor-transducer complexes. Collectively, our findings establish a direct arrestin recruitment mechanism in FZD receptors that shares key features with arrestin engagement in classical GPCRs, suggesting that the engagement of core GPCR transducers may modulate WNT signalling specificity. These insights position FZD receptors as druggable targets akin to classical GPCRs, opening new avenues for targeting FZD receptors for a wide range of diseases, including cancer.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786785","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}