Acta Pharmacologica Sinica最新文献

{"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}

{"title":"Tumor-driven arginine depletion induces T-cell metabolism reprogramming to suppress atherosclerosis in colorectal cancer.","authors":"Wen-Jun Ni, He-Yang Sun, Meng-Lei Chen, Yu-Zhang Shao, Cong-Cong Ma, Zhao-Yun Xu, Xue-Yu Wang, Shan Zhong, Wen-Xiu Li, Ying Zhang, Yue Wang, Jin-Wei Tian, Mei Hu, Yong Ji","doi":"10.1038/s41401-026-01899-2","DOIUrl":"https://doi.org/10.1038/s41401-026-01899-2","url":null,"abstract":"<p><p>The coexistence of atherosclerosis and cancer is increasingly common, yet the influence of tumors on atherogenesis remains poorly understood. In this study, we investigated the impact of colorectal cancer (CRC) on atherosclerosis and elucidated the underlying mechanisms. We analyzed clinical data from patients with concurrent atherosclerosis and CRC and established three murine models of atherosclerosis comorbidity: ApoE^-/- and Ldlr^-/- mice bearing subcutaneous MC38 tumors, and APC^min/+ApoE^-/- mice with spontaneous intestinal adenomas. We found that both patients and mice with concurrent tumors exhibited reduced plaque burden and enhanced plaque stability. Integrative multi-omics analysis comprising single-cell RNA sequencing, spatial transcriptomics, metabolomics, and bulk RNA sequencing revealed that tumors systemically deplete arginine, leading to adaptive metabolic reprogramming of intraplaque T cells toward an oxidative phosphorylation (OXPHOS)-dominant state. This metabolic shift was associated with reduced cytotoxic T-cell infiltration, suppressed pro-inflammatory effector programs, and weakened T cell-macrophage interactions, collectively establishing a low-inflammatory plaque microenvironment. Importantly, dietary arginine supplementation restored T-cell activation and reversed the CRC-mediated atheroprotective effects. These findings reveal a critical role of T-cell immunometabolic reprogramming in cancer-atherosclerosis comorbidity, demonstrate the pronounced context-dependent effects of arginine in advanced atherosclerosis, and highlight plaque-targeted immunometabolic interventions as a promising strategy to modulate plaque progression and stability.</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":"148786789","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":"Oxyberberine-nanoparticle attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating gut microbiota through suppressing CXCL10/CXCR3 pathway.","authors":"Yu-Lin Wu, Qing-Qing Xu, Ze-Hui Qin, Xue Wu, Zhen Hu, Wen Yang, Pei-Yao Ren, Yuan-Yang Tian, Zhi-Xiu Lin, Yan-Fang Xian","doi":"10.1038/s41401-026-01896-5","DOIUrl":"https://doi.org/10.1038/s41401-026-01896-5","url":null,"abstract":"<p><p>Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ₄₂) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.</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":"148786782","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":"PDE4D-CXCL13 axis in gland epithelial cells promotes B cell infiltration in primary Sjögren's syndrome.","authors":"Ru-Hong Fang, Mei-Yue Lu, Han-Shuang Liang, Xue-Jie Hu, Liu-Wei Chu, Chang Shu, Lan-Qi Du, Yu-Lin Jiang, Yan Cheng, De-Yun Liu, Xue-Lan-Ting Li, Lin-Li Yao, Xiang Lin, Xu Li, Pai-Pai Guo, Qing-Tong Wang","doi":"10.1038/s41401-026-01894-7","DOIUrl":"https://doi.org/10.1038/s41401-026-01894-7","url":null,"abstract":"<p><p>Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder characterized by immune cell, particularly B cell, infiltration into exocrine glands, where autoantibody production disrupts glandular architecture and secretory function. Unraveling the mechanisms that drive this B cell trafficking could unveil innovative therapeutic avenues for pSS. We report that phosphodiesterase 4D (PDE4D) is markedly up-regulated in glandular epithelial cells from both pSS patients and murine models, correlating tightly with diminished saliva output and heightened B cell infiltration. Mechanistically, lipopolysaccharide (LPS) engages Toll-like receptor 2/4 signaling in human salivary gland epithelial cells to induce PDE4D expression. Then, PDE4D reduces the phosphorylation of FOXO1 and enhances its nuclear translocation and stability; in turn, FOXO1 amplifies C-X-C motif chemokine ligand 13 (CXCL13) secretion that promotes B cell chemotaxis. To interrogate the functional relevance of PDE4D, we generated pSS models in PDE4D-knockout and wild-type (WT) mice, and additionally treated WT-pSS mice with a selective PDE4D inhibitor. Genetic deletion or pharmacologic inhibition of PDE4D augmented PKA-mediated FOXO1 phosphorylation, suppressed CXCL13 expression in glandular epithelial cells, and significantly attenuated disease manifestations. Collectively, our findings position PDE4D as a promising therapeutic target for pSS.</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":"148786754","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":"BDKRB2 upregulation by dystrophic microglia drives pain hypersensitivity in aged mice.","authors":"An Liu, Ming-Jun Zhang, Jin-Rong Guo, Han Chu, Song-Bin Liu, Dan-Yang Chen, Yuan-Zhong Kai, Peng Cao, Zhi Zhang","doi":"10.1038/s41401-026-01907-5","DOIUrl":"https://doi.org/10.1038/s41401-026-01907-5","url":null,"abstract":"<p><p>Although pain sensitization is among the most common conditions affecting the elderly, its underlying neural mechanisms remain unclear. Here, we found that mechanical hypersensitivity arises from enhanced glutamatergic excitability in primary somatosensory cortex due to bradykinin receptor B2 (BDKRB2) upregulation by dystrophic microglia during aging. Specifically, in vivo fiber photometry in aged mice revealed hyperactivity of glutamatergic neurons in primary somatosensory cortex of hindlimb (S1HL^Glu), while chemogenetic inhibition of these neurons reverses pain hypersensitivity in aged mice. BDKRB2 expression on S1HL^Glu neurons is significantly increased in aged mice, whereas its conditional knockdown restores pain sensitization, and its overexpression leads to nociceptive hypersensitivity in young mice. Moreover, chemogenetic or pharmacological inhibition of dystrophic microglia in aged mice reduces BDKRB2 levels, alleviating pain hypersensitivity. The present study thus demonstrates that microglia-mediated S1HL^Glu hyperactivity drives development of aging-related pain via BDKRB2 signaling, suggesting several potentially effective therapeutic targets for treating geriatric pain.</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":"148786813","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}