Acta Pharmacologica Sinica最新文献

{"title":"Krüppel-like factor 9 alleviates Alzheimer's disease via IDE-mediated Aβ degradation.","authors":"Yue-Yao Feng, Jing-Ran Hao, Yu-Jie Zhang, Tong-Tong Qiu, Meng-Lin Zhang, Wei Qiao, Jin-Jin Wu, Ping Qiu, Chao-Fan Xu, Yin-Liang Zhang, Chun-Yuan Du, Zhe Pan, Yong-Sheng Chang","doi":"10.1038/s41401-025-01491-0","DOIUrl":"10.1038/s41401-025-01491-0","url":null,"abstract":"<p><p>The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer's disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9^-/-) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9^-/- mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9^-/- mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1556-1566"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439704","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":"GABA transporter 1 is a promising drug target for CUL4B mutation-associated epilepsy.","authors":"Wei Jiang, Yan-Yan Ma, Yu-Feng Wang, Shi-Qi Jin, Rui-Qi Yu, Shu-Xian Chu, Yang-Fan Gao, Mo-Lin Wang, Yong-Xin Zou, Qiao Liu, Yu Song, Yan Zheng, Chen Zhang, Gong-Ping Sun, Bai-Chun Jiang, Yao-Qin Gong","doi":"10.1038/s41401-025-01490-1","DOIUrl":"10.1038/s41401-025-01490-1","url":null,"abstract":"<p><p>Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene result in syndromic X-linked intellectual disability (XLID). In addition to intellectual disability, patients with CUL4B mutations exhibit epilepsy. To date, the mechanism underlying epilepsy associated with CUL4B mutation has not been elucidated. Here, we show that male mice with Cul4b deleted in the nervous system are more susceptible to both pentylenetetrazole (PTZ)- and kainic acid (KA)-induced epilepsy and exhibit spontaneous epilepsy without any chemical inducers. We identify the CRL4B complex as an E3 ubiquitin ligase that targets GABA transporter 1 (GAT1). CUL4B deletion in male mice results in GAT1 accumulation and increased GABA reuptake, leading to impaired GABA-mediated inhibitory synaptic transmission. Treating CUL4B-deficient mice with the GAT1 inhibitor tiagabine effectively reverses the increased susceptibility to chemical-induced epilepsy and attenuates spontaneous epilepsy without the use of chemical inducers. We further confirm the role of CUL4B in the regulation of GAT1 levels and GABA uptake in neurons and astrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from patients with CUL4B loss-of-function mutations. Our work reveals a novel mechanism underlying the pathogenesis of epilepsy and identifies a promising drug target for treating CUL4B mutation-associated epilepsy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1580-1591"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472089","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":"Discovery of 5-imidazole-3-methylbenz[d]isoxazole derivatives as potent and selective CBP/p300 bromodomain inhibitors for the treatment of acute myeloid leukemia.","authors":"Jian-Kang Hu, Xin Tang, Guo-Long Luo, Cheng Zhang, Tian-Bang Wu, Chao Wang, Hui Shen, Xiao-Fan Zhao, Xi-Shan Wu, Jeff B Smaill, Yong Xu, Yan Zhang, Qiu-Ping Xiang","doi":"10.1038/s41401-025-01478-x","DOIUrl":"10.1038/s41401-025-01478-x","url":null,"abstract":"<p><p>Inhibition of the bromodomain of the cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 is an attractive therapeutic approach in oncology, particularly in acute myeloid leukemia (AML). In this study we describe the design, optimization, and evaluation of 5-imidazole-3-methylbenz[d]isoxazoles as novel, potent and selective CBP/p300 bromodomain inhibitors. Two of the representative compounds, 16t (Y16524) and 16u (Y16526), bound to the p300 bromodomain with IC₅₀ values of 0.01 and 0.03 μM, respectively. Furthermore, 16t and 16u potently inhibited the growth of AML cell lines, particularly MV4;11 cells with IC₅₀ values of 0.49 and 0.26 μM, respectively. The potent CBP/p300 bromodomain inhibitors represent a new class of compounds for the development of potential therapeutics against AML.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1706-1721"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073258","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":"METTL14-mediated m⁶A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction.","authors":"Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang","doi":"10.1038/s41401-025-01485-y","DOIUrl":"10.1038/s41401-025-01485-y","url":null,"abstract":"<p><p>N⁶-methyladenosine (m⁶A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m⁶A modification promotes the development and progression of cardiomyocyte pyroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1639-1651"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405120","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":"Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.","authors":"Si-Yuan Shen, Chao Wu, Zhi-Qian Yang, Ke-Xin Wang, Zhen-Hua Shao, Wei Yan","doi":"10.1038/s41401-024-01472-9","DOIUrl":"10.1038/s41401-024-01472-9","url":null,"abstract":"<p><p>The medicinal and recreational uses of Cannabis sativa have been recognized for thousands of years. Today, cannabis-derived medicines are used to treat a variety of conditions, including chronic pain, epilepsy, multiple sclerosis, and chemotherapy-induced nausea. However, cannabis use disorder (CUD) has become the third most prevalent substance use disorder globally. Cannabinoid receptors are the primary targets that mediate the effects of cannabis and its analogs. Despite their importance, the mechanisms of modulation and the full therapeutic potential of cannabinoid receptors remain unclear, hindering the development of the next generation of cannabinoid-based drugs. This review summarizes the discovery and medicinal potential of phytocannabinoids and explores the distribution, signaling pathways, and functional roles of cannabinoid receptors. It also discusses classical cannabinoid drugs, as well as agonists, antagonists, and inverse agonists, which serve as key therapeutic agents. Recent advancements in the development of allosteric drugs are highlighted, with a focus on positive and negative allosteric modulators (PAMs and NAMs) that target CB1 and CB2 receptors. The identification of multiple allosteric sites on the CB1 receptor and the structural basis for allosteric modulation are emphasized, along with the structure-based discovery of ago-BAMs for CB1. This review concludes by examining the future potential of allosteric modulators in cannabinoid drug development, noting that ongoing progress in cannabinoid-derived drugs continues to open new avenues for therapeutic use and paves the way for future research into their full medicinal potential.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1495-1510"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254037","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":"Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit.","authors":"Jun-Hao Deng, Hong-Yue Li, Zi-Yang Liu, Jing-Pei Liang, Ying Ren, Yuan-Ying Zeng, Ya-Li Wang, Xin-Liang Mao","doi":"10.1038/s41401-025-01481-2","DOIUrl":"10.1038/s41401-025-01481-2","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is difficult to treat and novel therapeutic targets remain to be identified. TRIP13, an AAA+ ATPase, is highly expressed in breast cancer and predicts poor prognosis; however, the specific mechanism is not fully understood. In the present study, we found TRIP13 promotes TNBC cell viability and migration. In a mechanistic study, TRIP13 is found to activate STAT3 but not other STAT members. Out of expectation, TRIP13 is found to be upregulated by STAT3 and STAT3 specifically recognizes and binds to the STAT3-recognition element in the regulatory region of TRIP13. Moreover, we found bardoxolone, a recently approved drug for the treatment of chronic kidney disease, displays potent activity by inhibiting STAT3 activation and downregulating TRIP13. Furthermore, bardoxolone inhibits breast cancer cell proliferation and migration, and induces apoptosis. Consistent with this finding, ectopic expression of TRIP13 ablates bardoxolone-induced breast cancer cell apoptosis. Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1733-1741"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405113","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":"Circular RNA hsa_circ_0000288 protects against epilepsy in mice by binding to and stabilizing caprin1 protein.","authors":"Lin Guo, Na Lv, Jian-Lun Ji, Ce Gao, Si-Yu Liu, Zi-Yu Liu, Xin-Ting Lin, Zhi-Dong Liu, Yun Wang","doi":"10.1038/s41401-025-01486-x","DOIUrl":"10.1038/s41401-025-01486-x","url":null,"abstract":"<p><p>Current anti-epileptic drugs remain to be unsatisfactory, new therapeutic approaches are needed. Circular RNA is a promising class of therapeutic RNAs. Recent studies have shown the role of circRNA in the pathologic process of epilepsy. In this study, we identified the circRNA in epileptic patients in remission that inhibited the epileptic course. By comparing the profiles of differentially expressed circRNAs in peripheral serum between patients in remission and those not in remission, we found that the level of hsa_circ_0000288 (circ288) was markedly elevated in the epileptic patients in remission. We established a kainic acid-induced status epilepticus model in mice. Overexpression of Circ288 by injecting adeno-associated virus (AAV)-circ288-overexpression vector into hippocampi significantly ameliorated epilepsy-induced neuronal injury, promoted hippocampus neurogenesis, and inhibited abnormal migration of newborn neurons into the dentate hilus. Moreover, circ288 overexpression significantly decreased the epileptiform discharges and the spontaneous seizures in the chronic phase of epileptogenesis and alleviated mood disorders (anxiety, depression), and cognitive deficits in epileptic mice. We revealed that circ288 directly bound to an RNA-binding protein caprin1 and inhibited its degradation. The protective action of circ288 was reversed by the knockdown of caprin1 in an in vitro epileptic model and lost in the neuron-specific caprin1 knockout mice (CaMK2α-Cre:Caprin1^f/f). Overexpression of circ288 or caprin1 raised the mRNA level of NMDA receptor 3B, a negative modulator of NMDA receptors, suggesting the involvement of the carpin1-NMDA receptor 3B pathway in the role of circ288. Given the disadvantages of circ288 overexpression by a virus, we constructed exosomes-encapsulated circ288 (EXO-circ288) and demonstrated that tail vein injection of EXO-circ288 exerted robust protective effects. This study provides a new avenue for developing anti-epileptic therapeutic RNAs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1592-1609"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439701","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":"Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism.","authors":"Wei-Ting Cheng, Si-Ya Pei, Jie Wu, Yan-Jie Wang, Yong-Wen Yang, Mei-Fang Xiao, Jun Chen, Yuan-Yuan Wang, Li Wu, Ze-Bing Huang","doi":"10.1038/s41401-025-01495-w","DOIUrl":"10.1038/s41401-025-01495-w","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R^-/- mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R^-/- mice. The gut dysbiosis in CB2R^-/- mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R^-/- mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R^-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1676-1691"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466623","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":"SEC62-dependent ER-phagy contributes to apelin-13/APJ-induced monocyte-vascular endothelial cell adhesion in atherosclerosis pathogenesis.","authors":"Zhe Chen, Jun Cheng, Qun Zhou, Le-le Wu, Jia-Wei Chen, Xiang-Ning Duan, Jia-Long Yan, Jian-Gang Cao, Xiao-Dan Xia, Lan-Fang Li, Lin-Xi Chen","doi":"10.1038/s41401-024-01471-w","DOIUrl":"10.1038/s41401-024-01471-w","url":null,"abstract":"<p><p>The monocyte adhesion to vascular endothelial cells constitutes a key step in atherosclerosis pathogenesis. We previously found that ROS-autophagy pathway participated in the monocyte-endothelial cell adhesion induced by angiotensin domain type 1 receptor-associated proteins (APJ) and its endogenous ligand apelin-13. In this study, we investigated what specific type of autophagy apelin-13 regulated in this process. By conducting full-scale transcriptomic analysis in apelin-13-treated human umbilical vein endothelial cells (HUVECs), we found that the transcription levels of ER-phagy receptor protein SEC62 were significantly elevated. Importantly, SEC62 was also upregulated in human atherosclerotic lesions. Thus, we investigated the effects of SEC62-dependent ER-phagy on apelin-13-induced monocyte-endothelial cell adhesion and atherosclerosis pathogenesis. We demonstrated that Apelin-13 (0.001-1 μM) dose-dependently upregulated SEC62 expression thereby inducing ER-phagy in HUVECs. This effect was reversed by autophagy inhibitor 3MA (10 mM) and endoplasmic reticulum stress inhibitor salubrinal (10 μM). The siRNA-Sec62, 3MA (10 mM), and salubrinal (10 μM) all inhibited apelin-13-induced monocyte-endothelial cells adhesion, whereas vascular endothelial cells specific SEC62 deletion alleviated atherosclerotic plaques area, intercellular adhesion molecules expression and lesional macrophages in apelin-13-treated APOE^-/- mice with high-fat and high-cholesterol diet. Moreover, we demonstrated that ubiquitin-like modification of ALDH1L1 was involved in SEC62-dependent ER-phagy in apelin-13-treated HUVECs: apelin-13 upregulated small ubiquitin-like protein UBL4A, which mediated the ubiquitination-like modification of ALDH1L1 at 812-lysine site. This, in turn, promoted insertion of ALDH1L1 into ER membrane and led to SEC62-dependent ER-phagy. We showed that siRNA-UBL4A, siRNA-ALDH1L1, siRNA-ASNA1, and the mutant of 812 lysine site of ALDH1L1 all decreased apelin-13-induced monocyte-endothelial cell adhesion. We conclude that apelin-13 induces SEC62-dependent ER-phagy to promote monocyte-endothelial cell adhesion and atherosclerosis. This study reveals new mechanisms underlying atherosclerosis and identifies a potential therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1652-1663"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389835","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":"CXCR2 modulates chronic pain comorbid depression in mice by regulating adult neurogenesis in the ventral dentate gyrus.","authors":"Xiao-Jie Li, Shuo Wu, Zi-Han Liu, An-An Liu, Hui-Sheng Peng, Yu-Jun Wang, Ye-Xiang Chen, Jing-Gen Liu, Chi Xu","doi":"10.1038/s41401-025-01496-9","DOIUrl":"10.1038/s41401-025-01496-9","url":null,"abstract":"<p><p>Research shows that chronic pain may induce depression-like behaviors through impairing adult hippocampal neurogenesis (AHN) in the ventral dentate gyrus (DG), whereas restoration of AHN may effectively alleviate depression. The C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor involved in various neural activities of the hippocampus including AHN. In this study we investigated the role of CXCR2 of neural stem cells (NSCs) in the ventral DG in regulating both AHN and depression-like behaviors of mice with chronic neuropathic pain. Chronic neuropathic pain was induced in mice by the spared nerve injury (SNI) surgery; mechanical allodynia and depression-like behaviors were monitored, then mouse DG was collected for analysis. We observed that chronic neuropathic pain significantly decreased the number of immature neurons in the ventral DG by inhibiting the neuronal differentiation of NSCs; specific overexpression of CXCR2 in NSCs by injecting the adeno-associated virus (AAV) into the DG restored adult neurogenesis accompanied by alleviated depression-like behaviors in SNI mice. In contrast, the knockdown of CXCR2 in hippocampal NSCs of naive mice was sufficient to inhibit adult neurogenesis, inducing depression-like behaviors. Moreover, we found that the Wnt3a/β-catenin pathway was downregulated in the ventral DG of SNI mice, which was restored after CXCR2 overexpression or infusing a CXCR2 agonist CXCL1 into the ventral DG. We conclude that CXCR2 expressed in hippocampal NSCs is crucial for regulating adult neurogenesis and chronic pain-induced depression-like behavior, thus representing a new target for the treatment of chronic pain comorbid depression.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1567-1579"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456574","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}