Pub Date : 2026-01-24DOI: 10.1016/j.ejphar.2026.178597
Suhan Zhou , Honghong Wang , Huanhuan Zhu , Shilong Xiang , Minjing Zhang , Meifang Wang , Weilian Feng , Guizhen Yu , Bingjue Li , Fanghao Cai , Jingyi Zhou , Zheng Li , Runzhi Zhu , Xiang Yan , Jianghua Chen , En Yin Lai , Gensheng Zhang , Fei Han
Background
Emerging evidence highlights the critical role of ferroptosis in the pathophysiology of both acute kidney injury (AKI) and chronic kidney disease (CKD). Nuclear factor erythroid 2-related factor 2 (Nrf2), which is activated through pathways involving Takeda G protein-coupled receptor 5 (TGR5), has emerged as a potential therapeutic target to inhibit ferroptosis.
Methods
We evaluated kidney TGR5 expression and urinary TGR5 excretion in AKI patients, as well as in vivo (mouse) and in vitro (cellular) models of AKI induced by ischemia-reperfusion (IR) injury and subsequent CKD. Correlation analyses were conducted with renal function markers. Cellular injury models were established using human renal proximal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVECs). The TGR5 agonist INT-777 was used to activate TGR5 signaling. Morphological changes in kidney tissues and cells were examined by transmission electron microscopy, and intracellular ferrous iron (Fe2+) levels, reactive oxygen species (ROS), and malondialdehyde (MDA) were quantified with commercial assay kits.
Results
Decreased kidney TGR5 expression and increased urinary TGR5 excretion were observed in AKI patients and experimental models, both correlating significantly with impaired renal function. Importantly, treatment with the TGR5 agonist INT-777 activated the TGR5/cAMP/PKA/Nrf2 pathway, suppressed oxidative stress and ferroptosis, and thereby attenuated synchronous injury in tubular epithelial and endothelial cells.
Conclusions
This study offers novel insights into ferroptosis mechanisms in AKI and subsequent CKD, identifying TGR5 as a promising therapeutic target.
背景：新出现的证据强调了铁下垂在急性肾损伤（AKI）和慢性肾脏疾病（CKD）的病理生理中的关键作用。通过武田G蛋白偶联受体5 （Takeda G protein coupled receptor 5, TGR5）通路激活的核因子红系2相关因子2 （Nrf2）已成为抑制铁凋亡的潜在治疗靶点。方法：我们评估了AKI患者肾脏TGR5的表达和尿TGR5的排泄，以及由缺血再灌注（IR）损伤引起的AKI和随后的CKD的体内（小鼠）和体外（细胞）模型。与肾功能指标进行相关性分析。采用人肾近端小管上皮细胞（HK-2）和人脐静脉内皮细胞（HUVECs）建立细胞损伤模型。TGR5激动剂INT-777用于激活TGR5信号。透射电镜观察肾脏组织和细胞的形态学变化，并用商业检测试剂盒定量细胞内亚铁（Fe2+）水平、活性氧（ROS）和丙二醛（MDA）。结果：AKI患者及实验模型肾脏TGR5表达降低，尿TGR5排泄量增加，均与肾功能受损显著相关。重要的是，TGR5激动剂INT-777激活TGR5/cAMP/PKA/Nrf2通路，抑制氧化应激和铁凋亡，从而减轻小管上皮和内皮细胞的同步损伤。结论：这项研究为AKI和随后的CKD的铁下垂机制提供了新的见解，确定了TGR5是一个有希望的治疗靶点。
{"title":"TGR5 rescues renal ischemia-reperfusion injury by suppressing ferroptosis and cAMP/PKA/Nrf2 axis","authors":"Suhan Zhou , Honghong Wang , Huanhuan Zhu , Shilong Xiang , Minjing Zhang , Meifang Wang , Weilian Feng , Guizhen Yu , Bingjue Li , Fanghao Cai , Jingyi Zhou , Zheng Li , Runzhi Zhu , Xiang Yan , Jianghua Chen , En Yin Lai , Gensheng Zhang , Fei Han","doi":"10.1016/j.ejphar.2026.178597","DOIUrl":"10.1016/j.ejphar.2026.178597","url":null,"abstract":"<div><h3>Background</h3><div>Emerging evidence highlights the critical role of ferroptosis in the pathophysiology of both acute kidney injury (AKI) and chronic kidney disease (CKD). Nuclear factor erythroid 2-related factor 2 (Nrf2), which is activated through pathways involving Takeda G protein-coupled receptor 5 (TGR5), has emerged as a potential therapeutic target to inhibit ferroptosis.</div></div><div><h3>Methods</h3><div>We evaluated kidney TGR5 expression and urinary TGR5 excretion in AKI patients, as well as <em>in vivo</em> (mouse) and <em>in vitro</em> (cellular) models of AKI induced by ischemia-reperfusion (IR) injury and subsequent CKD. Correlation analyses were conducted with renal function markers. Cellular injury models were established using human renal proximal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVECs). The TGR5 agonist INT-777 was used to activate TGR5 signaling. Morphological changes in kidney tissues and cells were examined by transmission electron microscopy, and intracellular ferrous iron (Fe<sup>2+</sup>) levels, reactive oxygen species (ROS), and malondialdehyde (MDA) were quantified with commercial assay kits.</div></div><div><h3>Results</h3><div>Decreased kidney TGR5 expression and increased urinary TGR5 excretion were observed in AKI patients and experimental models, both correlating significantly with impaired renal function. Importantly, treatment with the TGR5 agonist INT-777 activated the TGR5/cAMP/PKA/Nrf2 pathway, suppressed oxidative stress and ferroptosis, and thereby attenuated synchronous injury in tubular epithelial and endothelial cells.</div></div><div><h3>Conclusions</h3><div>This study offers novel insights into ferroptosis mechanisms in AKI and subsequent CKD, identifying TGR5 as a promising therapeutic target.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178597"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178601
Yuxiu Zhang , Panpan Lei , Jinna Liang , Sifan Xie , Xiaoyu Ma , Weina Ma
Non-small cell lung cancer (NSCLC) remains the leading contributor to cancer mortality, and its relentless progression is partly fueled by the overexpression of α1-type I collagen (COL1A1), an extracellular-matrix protein whose abundance herald dismal prognosis and shorter survival. Here, we establish COL1A1 as a bona fide oncogenic driver: genetic silencing attenuates NSCLC proliferation and migratory capacity, whereas enforced expression accelerates both phenotypes. Exploiting this vulnerability, we identify bufotalin (BT), a bufadienolide extracted from the traditional remedy Chansu, as a selective and potent inhibitor of COL1A1-high NSCLC. BT physically engages COL1A1, triggering its post-transcriptional down-regulation and concomitantly crippling malignant fitness. Mechanistically, BT simultaneously disables the PTEN/AKT/mTOR and Ras/MEK/ERK cascades, enforces G2–M arrest via Cyclin B1/CDK1 dysregulation, and quells epithelial-to-mesenchymal transition by restoring E-cadherin while repressing N-cadherin, MMP3, and MMP9. Beyond tumoricidal action, BT reshapes the tumor microenvironment: it suppresses TGF-β secretion, deactivates cancer-associated fibroblasts (CAFs), and severs the pro-tumorigenic COL1A1–integrin α11(ITGA11) paracrine circuit. Notably, COL1A1 reconstitution rescues CAF-induced tumor progression, underscoring COL1A1 dependency. Collectively, our findings position BT as a first-in-class COL1A1 antagonist that exerts dual cytotoxic and microenvironment-normalizing effects, providing a rational therapeutic avenue for NSCLC.
{"title":"Bufotalin targets COL1A1 to suppress non-small cell lung cancer growth and remodel the tumor microenvironment via dual inhibition of PI3K/AKT/mTOR and MAPK pathways","authors":"Yuxiu Zhang , Panpan Lei , Jinna Liang , Sifan Xie , Xiaoyu Ma , Weina Ma","doi":"10.1016/j.ejphar.2026.178601","DOIUrl":"10.1016/j.ejphar.2026.178601","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains the leading contributor to cancer mortality, and its relentless progression is partly fueled by the overexpression of α1-type I collagen (COL1A1), an extracellular-matrix protein whose abundance herald dismal prognosis and shorter survival. Here, we establish COL1A1 as a bona fide oncogenic driver: genetic silencing attenuates NSCLC proliferation and migratory capacity, whereas enforced expression accelerates both phenotypes. Exploiting this vulnerability, we identify bufotalin (BT), a bufadienolide extracted from the traditional remedy Chansu, as a selective and potent inhibitor of COL1A1-high NSCLC. BT physically engages COL1A1, triggering its post-transcriptional down-regulation and concomitantly crippling malignant fitness. Mechanistically, BT simultaneously disables the PTEN/AKT/mTOR and Ras/MEK/ERK cascades, enforces G2–M arrest via Cyclin B1/CDK1 dysregulation, and quells epithelial-to-mesenchymal transition by restoring E-cadherin while repressing N-cadherin, MMP3, and MMP9. Beyond tumoricidal action, BT reshapes the tumor microenvironment: it suppresses TGF-β secretion, deactivates cancer-associated fibroblasts (CAFs), and severs the pro-tumorigenic COL1A1–integrin α11(ITGA11) paracrine circuit. Notably, COL1A1 reconstitution rescues CAF-induced tumor progression, underscoring COL1A1 dependency. Collectively, our findings position BT as a first-in-class COL1A1 antagonist that exerts dual cytotoxic and microenvironment-normalizing effects, providing a rational therapeutic avenue for NSCLC.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178601"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178602
Elsayed A. Elmorsy , Manal Mohamed Hatem , Hamad Alsaykhan , Abdulaziz A. Alsalloom , Mostafa M. Khodeir , Mohammed Alorini , Rabab S. Hamad , Alshaimaa A. Farrag , Mohamed A.M. Ali , Norah Suliman Alsoqih , Omar Almansour , Mariam S. Alharbi , Ahmad H. Alhowail , Hesham Saad Ata , Basem H. Elesawy , Ahmed Sameh , Sameh Saber
Steatohepatitis links cholesterol-crystal injury to ATP-gated purinergic signaling, culminating in NF-κB/NLRP3 inflammasome activation and metabolic dysfunction. We posited that dissolving cholesterol burden while concurrently blocking P2X7 would reprogram lysosomal–purinergic crosstalk and outperform single-pathway therapy. In a streptozotocin–high-fat-diet diabetic rat model, hydroxypropyl-β-cyclodextrin (HPβCD; cholesterol efflux/crystal dissolution) combined with the P2X7 antagonist coomassie brilliant blue G-250 (CBB) improved glucose tolerance, fasting glycemia, and HOMA-IR beyond either monotherapy. In addition, this dual intervention lowered transaminases and inflammatory cytokines; reduced hepatic fibrosis and lipid overload; and restored lysosomal and insulin-signaling readouts. Mechanistically, dual treatment most effectively suppressed the P2X7–Panx1 axis, restored lysosomal integrity (increased LAMP1, decreased cathepsin-B), and curtailed NF-κB/NLRP3–GSDMD signaling, indicating disruption of the feed-forward loop connecting lysosomal injury with purinergic activation. Synergy at fixed in-vivo doses was formally quantified by HSA and Bliss, with the largest Bliss gains at purinergic–inflammasome nodes (P27RX, Panx1, NLRP3, p-AKT/AKT) and coherent effects at lysosomal biogenesis markers (LAMP1, TFEB). Integrative network analysis intersecting cholesterol-regulated genes with the P2RX7 interactome revealed an overlap enriched for IL-1β processing, pyroptosis, and lysosomal organization, nominating a high-connectivity P2RX7/Panx1–LAMP1/CTSB–NLRP3 module selectively reprogrammed by the combination. This work provides in-vivo evidence that simultaneously targeting cholesterol-crystal–driven lysosomal injury and ATP-gated P2X7 signaling yields mechanistic and therapeutic synergy, while linking systems-level network topology to multi-arm pharmacodynamics to define a reprogrammable lysosomal–purinergic module. Collectively, the data establish a mechanistically anchored, clinically plausible combination strategy for diabetes-associated steatohepatitis that surpasses single-pathway interventions.
{"title":"Reprogramming lysosomal–purinergic crosstalk governs the synergistic attenuation of NLRP3 inflammasome activation by cyclodextrin–P2X7 blockade in diabetic rats","authors":"Elsayed A. Elmorsy , Manal Mohamed Hatem , Hamad Alsaykhan , Abdulaziz A. Alsalloom , Mostafa M. Khodeir , Mohammed Alorini , Rabab S. Hamad , Alshaimaa A. Farrag , Mohamed A.M. Ali , Norah Suliman Alsoqih , Omar Almansour , Mariam S. Alharbi , Ahmad H. Alhowail , Hesham Saad Ata , Basem H. Elesawy , Ahmed Sameh , Sameh Saber","doi":"10.1016/j.ejphar.2026.178602","DOIUrl":"10.1016/j.ejphar.2026.178602","url":null,"abstract":"<div><div>Steatohepatitis links cholesterol-crystal injury to ATP-gated purinergic signaling, culminating in NF-κB/NLRP3 inflammasome activation and metabolic dysfunction. We posited that dissolving cholesterol burden while concurrently blocking P2X7 would reprogram lysosomal–purinergic crosstalk and outperform single-pathway therapy. In a streptozotocin–high-fat-diet diabetic rat model, hydroxypropyl-β-cyclodextrin (HPβCD; cholesterol efflux/crystal dissolution) combined with the P2X7 antagonist coomassie brilliant blue G-250 (CBB) improved glucose tolerance, fasting glycemia, and HOMA-IR beyond either monotherapy. In addition, this dual intervention lowered transaminases and inflammatory cytokines; reduced hepatic fibrosis and lipid overload; and restored lysosomal and insulin-signaling readouts. Mechanistically, dual treatment most effectively suppressed the P2X7–Panx1 axis, restored lysosomal integrity (increased LAMP1, decreased cathepsin-B), and curtailed NF-κB/NLRP3–GSDMD signaling, indicating disruption of the feed-forward loop connecting lysosomal injury with purinergic activation. Synergy at fixed in-vivo doses was formally quantified by HSA and Bliss, with the largest Bliss gains at purinergic–inflammasome nodes (P27RX, Panx1, NLRP3, p-AKT/AKT) and coherent effects at lysosomal biogenesis markers (LAMP1, TFEB). Integrative network analysis intersecting cholesterol-regulated genes with the P2RX7 interactome revealed an overlap enriched for IL-1β processing, pyroptosis, and lysosomal organization, nominating a high-connectivity P2RX7/Panx1–LAMP1/CTSB–NLRP3 module selectively reprogrammed by the combination. This work provides in-vivo evidence that simultaneously targeting cholesterol-crystal–driven lysosomal injury and ATP-gated P2X7 signaling yields mechanistic and therapeutic synergy, while linking systems-level network topology to multi-arm pharmacodynamics to define a reprogrammable lysosomal–purinergic module. Collectively, the data establish a mechanistically anchored, clinically plausible combination strategy for diabetes-associated steatohepatitis that surpasses single-pathway interventions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178602"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178600
Yuqing Li , Haoqi Li , Zijie Cheng , Huimin Li , Yupeng Zhong , Xin Dong , Dan Wu , Qingxun Hu
Cardiovascular disease (CVD) is a major public health issue causing high mortality rates worldwide. Its pathogenesis is complex and diverse, its treatment costs are high, and it represents a serious threat to human health. In recent years, changes in amino acid metabolism have drawn widespread attention as a key part of regulating CVD. Among these amino acids, glutamine (Gln)—the most abundant free amino acid in the body — has gradually shown important potential in the cardiovascular system, both in terms of its metabolic activity and its role in functional regulation. As new technologies like spatiotemporal metabolomics and single-cell metabolic imaging have developed, they have provided new ways to systematically analyze the dynamic distribution and regulatory mechanisms of Gln in the tissue microenvironment. This paper reviews Gln's metabolic pathways in the body and how it works in maintaining cardiovascular balance and in disease states, including ferroptosis, oxidative stress (OS), and inflammatory regulation. It also looks at, based on current research, how Gln might help treat different CVD models and its potential value in practical use. Finally, this paper suggests that future research should combine metabolomics methods with higher temporal and spatial resolution. This will help further identify the key metabolic nodes and pathways of Gln in CVD development, and provide theoretical support and technical ways to develop precise treatment plans based on regulating amino acid metabolism.
{"title":"The role of glutamine metabolism in cardiovascular diseases","authors":"Yuqing Li , Haoqi Li , Zijie Cheng , Huimin Li , Yupeng Zhong , Xin Dong , Dan Wu , Qingxun Hu","doi":"10.1016/j.ejphar.2026.178600","DOIUrl":"10.1016/j.ejphar.2026.178600","url":null,"abstract":"<div><div>Cardiovascular disease (CVD) is a major public health issue causing high mortality rates worldwide. Its pathogenesis is complex and diverse, its treatment costs are high, and it represents a serious threat to human health. In recent years, changes in amino acid metabolism have drawn widespread attention as a key part of regulating CVD. Among these amino acids, glutamine (Gln)—the most abundant free amino acid in the body — has gradually shown important potential in the cardiovascular system, both in terms of its metabolic activity and its role in functional regulation. As new technologies like spatiotemporal metabolomics and single-cell metabolic imaging have developed, they have provided new ways to systematically analyze the dynamic distribution and regulatory mechanisms of Gln in the tissue microenvironment. This paper reviews Gln's metabolic pathways in the body and how it works in maintaining cardiovascular balance and in disease states, including ferroptosis, oxidative stress (OS), and inflammatory regulation. It also looks at, based on current research, how Gln might help treat different CVD models and its potential value in practical use. Finally, this paper suggests that future research should combine metabolomics methods with higher temporal and spatial resolution. This will help further identify the key metabolic nodes and pathways of Gln in CVD development, and provide theoretical support and technical ways to develop precise treatment plans based on regulating amino acid metabolism.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178600"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178591
Marie H. Deventer , Silvia Mori , Marcus Angermann , Michael Decker , Christophe P. Stove
The excitatory neuropeptides orexin-A and -B interact with their target G protein-coupled receptors (GPCRs), the orexin 1 and orexin 2 (OX1 and OX2) receptors, which are widely expressed throughout the central nervous system. The orexin system plays a critical role in regulating several physiological processes such as sleep-wake cycles, feeding behaviour, and arousal, and is implicated in a variety of (neurological) disorders. In particular dysregulation of the orexin system is linked to sleep disorders such as narcolepsy (often associated with orexin deficiency) and insomnia (characterized by an overactivity of sleep-wake regulation). This has prompted a growing interest in orexin-targeting therapeutics. This study is the first to report the development of four OX1 and OX2 receptor luminescence bioassays based on functional complementation of a split-nanoluciferase enzyme, capable of monitoring β-arrestin 2 (βarr2) and Gαq recruitment to activated OX1 and OX2 receptors. These assays were successfully applied to evaluate the pharmacological profiles of both agonists and antagonists, including the endogenous ligands orexin-A and -B, the clinically approved small molecule antagonists suvorexant and daridorexant, as well as EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) and four other compounds described in literature to act at orexin receptors. The obtained receptor activation patterns and selectivity profiles were consistent with literature data, indicating the reliability and robustness of the assay systems. Overall, the newly developed assays expand the toolkit for orexin receptor research by allowing the characterization of both agonists and antagonists, thereby contributing to the functional characterization of potential new drug candidates for various pathological conditions.
{"title":"Sleep, wake, and signaling: Functional profiling of orexin agonists and antagonists using newly developed orexin β-arrestin 2 and miniGαq recruitment assays","authors":"Marie H. Deventer , Silvia Mori , Marcus Angermann , Michael Decker , Christophe P. Stove","doi":"10.1016/j.ejphar.2026.178591","DOIUrl":"10.1016/j.ejphar.2026.178591","url":null,"abstract":"<div><div>The excitatory neuropeptides orexin-A and -B interact with their target G protein-coupled receptors (GPCRs), the orexin 1 and orexin 2 (OX<sub>1</sub> and OX<sub>2</sub>) receptors, which are widely expressed throughout the central nervous system. The orexin system plays a critical role in regulating several physiological processes such as sleep-wake cycles, feeding behaviour, and arousal, and is implicated in a variety of (neurological) disorders. In particular dysregulation of the orexin system is linked to sleep disorders such as narcolepsy (often associated with orexin deficiency) and insomnia (characterized by an overactivity of sleep-wake regulation). This has prompted a growing interest in orexin-targeting therapeutics. This study is the first to report the development of four OX<sub>1</sub> and OX<sub>2</sub> receptor luminescence bioassays based on functional complementation of a split-nanoluciferase enzyme, capable of monitoring β-arrestin 2 (βarr2) and Gα<sub>q</sub> recruitment to activated OX<sub>1</sub> and OX<sub>2</sub> receptors. These assays were successfully applied to evaluate the pharmacological profiles of both agonists and antagonists, including the endogenous ligands orexin-A and -B, the clinically approved small molecule antagonists suvorexant and daridorexant, as well as EMPA (<em>N</em>-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-<em>N</em>-pyridin-3-ylmethyl-acetamide) and four other compounds described in literature to act at orexin receptors. The obtained receptor activation patterns and selectivity profiles were consistent with literature data, indicating the reliability and robustness of the assay systems. Overall, the newly developed assays expand the toolkit for orexin receptor research by allowing the characterization of both agonists and antagonists, thereby contributing to the functional characterization of potential new drug candidates for various pathological conditions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178591"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178598
Yutong Li , Xuan Dong , Ruixu Sun , Liangmeng Gao , Xingyu Song , Zhibin Huang , Ling Zuo , Hongwei Liu
Background
This study employed an integrative multi-omics strategy to investigate the potential role of inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) in chronic prostatitis and to identify potential therapeutic targets and drugs using a mendelian randomization (MR)-proteomics causal inference framework.
Objectives
To investigate the potential role of ITPR3 in chronic prostatitis and to identify potential therapeutic targets and drugs.
Methods
We harmonized multi-omics data from eQTLGen (blood eQTLs, n = 31,684), UKB-PPP (plasma pQTLs, n = 54,219), and FinnGen (GWAS for chronic prostatitis: the discovery cohort 4160 cases/130,139 controls and replication cohort 4743 cases/141,300 controls). A two-sample bidirectional MR approach was applied to assess causal relationships between druggable genes and chronic prostatitis. The SMR-HEIDI analysis was conducted to exclude linkage disequilibrium confounding, followed by co-expression network construction and functional enrichment analysis to explore biological pathways. ITPR3 inhibitors were predicted using the DSigDB platform, with binding affinity evaluated through molecular docking and ADME properties analyzed via the SwissADME.
Results
MR analysis revealed that each 1-standard deviation increase in genetically predicted ITPR3 expression was associated with a 32.8 % higher risk of chronic prostatitis (OR = 1.328, 95 % CI: 1.108–1.702, P < 0.001), which was further validated by SMR-HEIDI testing (HEIDI P > 0.05). Functional enrichment analysis suggested that ITPR3 may contribute to chronic prostatitis progression through TGF-β/SMAD7 inflammatory pathway and calcium signaling dysregulation, while co-expression network analysis indicated its association with Th17 cell differentiation. Molecular docking demonstrated high binding affinity between raloxifene and ITPR3, and ADME profiling indicated favorable oral bioavailability without significant CYP450 inhibition risk, complying with Lipinski's rule.
Conclusion
ITPR3 is a novel therapeutic target for chronic prostatitis, and the computational repurposing of raloxifene as its inhibitor warrants further experimental investigation. These findings provide new insights for developing clinical interventions in chronic prostatitis.
背景：本研究采用综合多组学策略研究肌醇1,4,5-三磷酸受体3型（ITPR3）在慢性前列腺炎中的潜在作用，并使用孟德尔随机化(MR)-蛋白质组学因果推理框架确定潜在的治疗靶点和药物。目的：探讨ITPR3在慢性前列腺炎中的潜在作用，寻找潜在的治疗靶点和药物。方法：我们统一了来自eQTLGen（血液eqtl， n = 31,684）、UKB-PPP（血浆pqtl， n = 54,219）和FinnGen（慢性前列腺炎GWAS：发现队列4160例/130,139例对照，复制队列4,743例/141,300例对照）的多组学数据。采用双样本双向MR方法评估可用药基因与慢性前列腺炎之间的因果关系。通过SMR-HEIDI分析排除连锁不平衡混淆，然后通过共表达网络构建和功能富集分析探索生物学途径。使用DSigDB平台预测ITPR3抑制剂，通过分子对接评估结合亲和力，通过SwissADME分析ADME特性。结果：MR分析显示，基因预测ITPR3表达每增加1个标准差，慢性前列腺炎的风险增加32.8% (OR = 1.328, 95% CI: 1.108-1.702, P < 0.001)， SMR-HEIDI检验进一步验证了这一点（HEIDI P < 0.05）。功能富集分析提示ITPR3可能通过TGF-β/SMAD7炎症通路和钙信号通路失调参与慢性前列腺炎的进展，共表达网络分析提示其与Th17细胞分化相关。分子对接显示雷洛昔芬与ITPR3具有较高的结合亲和力，ADME谱显示良好的口服生物利用度，无显著的CYP450抑制风险，符合Lipinski规则。结论：ITPR3是慢性前列腺炎的一个新的治疗靶点，雷洛昔芬作为其抑制剂的计算再利用值得进一步的实验研究。这些发现为制定慢性前列腺炎的临床干预措施提供了新的见解。
{"title":"Genomic and AI-driven discovery in chronic prostatitis: Causal role of ITPR3 and therapeutic repurposing of raloxifene","authors":"Yutong Li , Xuan Dong , Ruixu Sun , Liangmeng Gao , Xingyu Song , Zhibin Huang , Ling Zuo , Hongwei Liu","doi":"10.1016/j.ejphar.2026.178598","DOIUrl":"10.1016/j.ejphar.2026.178598","url":null,"abstract":"<div><h3>Background</h3><div>This study employed an integrative multi-omics strategy to investigate the potential role of <em>inositol 1,4,5-trisphosphate receptor type 3</em> (<em>ITPR3</em>) in chronic prostatitis and to identify potential therapeutic targets and drugs using a mendelian randomization (MR)-proteomics causal inference framework.</div></div><div><h3>Objectives</h3><div>To investigate the potential role of <em>ITPR3</em> in chronic prostatitis and to identify potential therapeutic targets and drugs.</div></div><div><h3>Methods</h3><div>We harmonized multi-omics data from eQTLGen (blood eQTLs, n = 31,684), UKB-PPP (plasma pQTLs, n = 54,219), and FinnGen (GWAS for chronic prostatitis: the discovery cohort 4160 cases/130,139 controls and replication cohort 4743 cases/141,300 controls). A two-sample bidirectional MR approach was applied to assess causal relationships between druggable genes and chronic prostatitis. The SMR-HEIDI analysis was conducted to exclude linkage disequilibrium confounding, followed by co-expression network construction and functional enrichment analysis to explore biological pathways. <em>ITPR3</em> inhibitors were predicted using the DSigDB platform, with binding affinity evaluated through molecular docking and ADME properties analyzed <em>via</em> the SwissADME.</div></div><div><h3>Results</h3><div>MR analysis revealed that each 1-standard deviation increase in genetically predicted ITPR3 expression was associated with a 32.8 % higher risk of chronic prostatitis (OR = 1.328, 95 % CI: 1.108–1.702, <em>P</em> < 0.001), which was further validated by SMR-HEIDI testing (HEIDI <em>P</em> > 0.05). Functional enrichment analysis suggested that <em>ITPR3</em> may contribute to chronic prostatitis progression through <em>TGF-β</em>/<em>SMAD7</em> inflammatory pathway and calcium signaling dysregulation, while co-expression network analysis indicated its association with Th17 cell differentiation. Molecular docking demonstrated high binding affinity between raloxifene and <em>ITPR3</em>, and ADME profiling indicated favorable oral bioavailability without significant <em>CYP450</em> inhibition risk, complying with Lipinski's rule.</div></div><div><h3>Conclusion</h3><div><em>ITPR3</em> is a novel therapeutic target for chronic prostatitis, and the computational repurposing of raloxifene as its inhibitor warrants further experimental investigation. These findings provide new insights for developing clinical interventions in chronic prostatitis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178598"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178595
Fengyi Weng , Bin Zou , Jing Zhao , Jiamin Cui , Fengling Li , Dongming Yan , Xiaoqing Xu , Shuang Zhang , Yue Li , Jingyi Jin , Furong Qiu
The crosstalk between hepatocytes and macrophages is a key mechanism driving the pathogenesis of cholestatic liver injury (CLI). Glycyrrhetinic acid (GA), a bioactive compound derived from licorice, offers protection against CLI, but its effect on hepatocyte-macrophage crosstalk is not fully understood. This study aims to clarify the anti-inflammatory mechanisms of GA in blocking hepatocyte-macrophage interactions and identify its potential therapeutic targets. Wild-type mice was administrated α-naphthyl isothiocyanate (ANIT) intragastrically to induce CLI. The anti-inflammatory effects of GA were assessed by hepatic pathology, serum biochemistry, inflammatory cytokines expression, and modulation of acHMGB1/TLR2 axis. To recapitulate hepatocyte-macrophage crosstalk, primary mouse hepatocyte and macrophage was separately challenged with taurocholic acid (TCA) or HMGB1, co-treated with GA. Lastly, the contribution of TLR2 to the therapeutic action of GA was confirmed in TLR2-silenced RAW264.7 cells and Tlr2−/− cholestasis model mice. The results showed that GA dose-dependently attenuated CLI and alleviated inflammatory responses, as corroborated by suppressed expression of hepatic pro-inflammatory cytokines and diminished inflammatory cells infiltration. Concurrently, GA lowered circulating HMGB1 and blunted hepatic TLR2/NF-κB pathway. Moreover, GA inhibited TCA-induced acHMGB1 release in hepatocytes, and reduced inflammatory responses in Raw264.7 cells stimulated by HMGB1. Silencing or pharmacologically inhibiting TLR2 abolished the anti-inflammatory activity of GA in RAW264.7 cells, and Tlr2−/− mice displayed an attenuated responses to GA, confirming that TLR2 is an essential mediator of GA's hepatoprotective effect. In conclusion, this study reveals that GA alleviates CLI by blocking acHMGB1/TLR2 axis, thereby interrupting crosstalk between hepatocytes and macrophages.
{"title":"Glycyrrhetinic acid ameliorates cholestatic liver injury by inhibiting acHMGB1/TLR2-mediated crosstalk between hepatocytes and macrophages","authors":"Fengyi Weng , Bin Zou , Jing Zhao , Jiamin Cui , Fengling Li , Dongming Yan , Xiaoqing Xu , Shuang Zhang , Yue Li , Jingyi Jin , Furong Qiu","doi":"10.1016/j.ejphar.2026.178595","DOIUrl":"10.1016/j.ejphar.2026.178595","url":null,"abstract":"<div><div>The crosstalk between hepatocytes and macrophages is a key mechanism driving the pathogenesis of cholestatic liver injury (CLI). Glycyrrhetinic acid (GA), a bioactive compound derived from licorice, offers protection against CLI, but its effect on hepatocyte-macrophage crosstalk is not fully understood. This study aims to clarify the anti-inflammatory mechanisms of GA in blocking hepatocyte-macrophage interactions and identify its potential therapeutic targets. Wild-type mice was administrated α-naphthyl isothiocyanate (ANIT) intragastrically to induce CLI. The anti-inflammatory effects of GA were assessed by hepatic pathology, serum biochemistry, inflammatory cytokines expression, and modulation of acHMGB1/TLR2 axis. To recapitulate hepatocyte-macrophage crosstalk, primary mouse hepatocyte and macrophage was separately challenged with taurocholic acid (TCA) or HMGB1, co-treated with GA. Lastly, the contribution of TLR2 to the therapeutic action of GA was confirmed in TLR2-silenced RAW264.7 cells and <em>Tlr2</em><sup><em>−/−</em></sup> cholestasis model mice. The results showed that GA dose-dependently attenuated CLI and alleviated inflammatory responses, as corroborated by suppressed expression of hepatic pro-inflammatory cytokines and diminished inflammatory cells infiltration. Concurrently, GA lowered circulating HMGB1 and blunted hepatic TLR2/NF-κB pathway. Moreover, GA inhibited TCA-induced acHMGB1 release in hepatocytes, and reduced inflammatory responses in Raw264.7 cells stimulated by HMGB1. Silencing or pharmacologically inhibiting TLR2 abolished the anti-inflammatory activity of GA in RAW264.7 cells, and <em>Tlr2</em><sup><em>−/−</em></sup> mice displayed an attenuated responses to GA, confirming that TLR2 is an essential mediator of GA's hepatoprotective effect. In conclusion, this study reveals that GA alleviates CLI by blocking acHMGB1/TLR2 axis, thereby interrupting crosstalk between hepatocytes and macrophages.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178595"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.ejphar.2026.178596
YuanYuan Wang , Chenxi Tu , Hao Qin, Yingying Ma, Yukai Yang, Yinhua Xiong, Liang Peng, Lin Zhang
Prostate cancer (PCa) is the most common and aggressive malignancy in males worldwide, with its progression influenced by multiple factors. Androgens, the primary regulators of prostate cell growth and physiology, play a pivotal role in PCa pathogenesis through the androgen receptor (AR) signaling pathway, thus earning PCa designations as a hormone-sensitive or hormone-dependent cancer. Current anti-androgen therapies (e.g., androgen deprivation therapy, ADT) have demonstrated initial effectiveness but ultimately failed to prevent progression to castration-resistant prostate cancer (CRPC). Previous research has predominantly focused on AR and its associated signaling pathways. However, UGT2B15 and UGT2B17, as key members of the human UDP-glucuronosyltransferase (UGT) family, serve as critical catalytic enzymes in androgen metabolism. They both efficiently convert androgens into more excretable glucuronidated metabolites, thereby modulating systemic hormone levels, primarily affecting the activation of AR. This article systematically explores the association between the UGT2B subfamily and hormone-dependent prostate cancer, covering various aspects such as gene function, regulatory mechanisms, disease progression, and diagnosis. It elucidates the different roles of UGT2B genes and reveals their significant potential in being developed into biomarkers and therapeutic targets, paving the way for improvements in precision medicine for prostate cancer.
{"title":"Remodeling of androgen metabolism network mediated by UGT2B: a new perspective on treatment resistance in prostate cancer","authors":"YuanYuan Wang , Chenxi Tu , Hao Qin, Yingying Ma, Yukai Yang, Yinhua Xiong, Liang Peng, Lin Zhang","doi":"10.1016/j.ejphar.2026.178596","DOIUrl":"10.1016/j.ejphar.2026.178596","url":null,"abstract":"<div><div>Prostate cancer (PCa) is the most common and aggressive malignancy in males worldwide, with its progression influenced by multiple factors. Androgens, the primary regulators of prostate cell growth and physiology, play a pivotal role in PCa pathogenesis through the androgen receptor (AR) signaling pathway, thus earning PCa designations as a hormone-sensitive or hormone-dependent cancer. Current anti-androgen therapies (e.g., androgen deprivation therapy, ADT) have demonstrated initial effectiveness but ultimately failed to prevent progression to castration-resistant prostate cancer (CRPC). Previous research has predominantly focused on AR and its associated signaling pathways. However, UGT2B15 and UGT2B17, as key members of the human UDP-glucuronosyltransferase (UGT) family, serve as critical catalytic enzymes in androgen metabolism. They both efficiently convert androgens into more excretable glucuronidated metabolites, thereby modulating systemic hormone levels, primarily affecting the activation of AR. This article systematically explores the association between the UGT2B subfamily and hormone-dependent prostate cancer, covering various aspects such as gene function, regulatory mechanisms, disease progression, and diagnosis. It elucidates the different roles of UGT2B genes and reveals their significant potential in being developed into biomarkers and therapeutic targets, paving the way for improvements in precision medicine for prostate cancer.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178596"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.ejphar.2026.178587
Shenyue Zhang , Shengbo Niu , Shengli An , Xinghai Cai , Xiangqian Lao
Background
Semaglutide has demonstrated significant weight loss benefits, but comprehensive evidence on its long-term efficacy and safety in non-diabetic adults with overweight or obesity remains limited. This meta-analysis provides updated evidence by incorporating oral semaglutide data, extended follow-up duration, and comprehensive subgroup analyses.
Methods
We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases from inception to April 30, 2024. Randomized controlled trials comparing semaglutide with placebo in non-diabetic adults with BMI ≥27 kg/m2 were included in this study. The Cochrane Risk of Bias 2 tool was used for quality assessment. Data were analyzed using RevMan v5.4. Sensitivity analyses were used to explore the sources of heterogeneity.
Results
Seven RCTs involving 5411 participants were included in this review. Semaglutide significantly reduced absolute weight (WMD -12.24 kg, 95 % CI -13.25 to −11.22), percentage weight change (WMD -12.15 %, 95 % CI -13.63 to −10.67), BMI (WMD -4.32 kg/m2, 95 % CI -4.75 to −3.89), and waist circumference (WMD -9.32 cm, 95 % CI -9.87 to −8.78). Semaglutide increased likelihood of achieving ≥5 % weight loss (RR 2.63, 95 % CI 2.12–3.25). Total adverse events were modestly but significantly elevated (RR 1.05, 95 % CI 1.01–1.09), primarily gastrointestinal symptoms. Serious adverse reactions were also higher (RR 1.33, 95 % CI 1.08–1.63).
Conclusions
Both oral and subcutaneous semaglutide significantly improve weight management in non-diabetic adults. While the safety profile is generally acceptable, elevated serious adverse events warrant careful patient selection and monitoring. Optimal outcomes occur with lifestyle interventions at doses ≥2.4 mg weekly.
背景：Semaglutide已显示出显著的减肥效果，但关于其对超重或肥胖的非糖尿病成人的长期疗效和安全性的综合证据仍然有限。本荟萃分析通过纳入口服西马鲁肽数据、延长随访时间和全面亚组分析提供了最新证据。方法：系统检索PubMed、Embase、Cochrane Library、Web of Science和ClinicalTrials.gov数据库，检索时间从成立到2024年4月30日。在BMI≥27 kg/m2的非糖尿病成年人中比较西马鲁肽和安慰剂的随机对照试验纳入了本研究。采用Cochrane风险偏倚2工具进行质量评估。使用RevMan v5.4对数据进行分析。敏感性分析用于探索异质性的来源。结果：本综述纳入了7项随机对照试验，涉及5,411名受试者。Semaglutide显著降低绝对体重（WMD -12.24 kg, 95% CI -13.25 ~ -11.22）、体重变化百分比（WMD -12.15%, 95% CI -13.63 ~ -10.67）、BMI （WMD -4.32 kg/m2, 95% CI -4.75 ~ -3.89）和腰围（WMD -9.32 cm, 95% CI -9.87 ~ -8.78）。Semaglutide增加了达到≥5%体重减轻的可能性（RR 2.63, 95% CI 2.12-3.25）。总不良事件轻微但显著升高（RR 1.05, 95% CI 1.01-1.09），主要是胃肠道症状。严重不良反应也较高（RR 1.33, 95% CI 1.08-1.63）。结论：口服和皮下注射西马鲁肽均可显著改善非糖尿病成人的体重管理。虽然安全性一般可以接受，但严重不良事件的增加需要仔细选择和监测患者。最佳结果发生在剂量≥2.4 mg每周的生活方式干预。
{"title":"Efficacy and safety of semaglutide in non-diabetic adults with overweight or obesity: A meta-analysis of randomized controlled trials","authors":"Shenyue Zhang , Shengbo Niu , Shengli An , Xinghai Cai , Xiangqian Lao","doi":"10.1016/j.ejphar.2026.178587","DOIUrl":"10.1016/j.ejphar.2026.178587","url":null,"abstract":"<div><h3>Background</h3><div>Semaglutide has demonstrated significant weight loss benefits, but comprehensive evidence on its long-term efficacy and safety in non-diabetic adults with overweight or obesity remains limited. This meta-analysis provides updated evidence by incorporating oral semaglutide data, extended follow-up duration, and comprehensive subgroup analyses.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> databases from inception to April 30, 2024. Randomized controlled trials comparing semaglutide with placebo in non-diabetic adults with BMI ≥27 kg/m<sup>2</sup> were included in this study. The Cochrane Risk of Bias 2 tool was used for quality assessment. Data were analyzed using RevMan v5.4. Sensitivity analyses were used to explore the sources of heterogeneity.</div></div><div><h3>Results</h3><div>Seven RCTs involving 5411 participants were included in this review. Semaglutide significantly reduced absolute weight (WMD -12.24 kg, 95 % CI -13.25 to −11.22), percentage weight change (WMD -12.15 %, 95 % CI -13.63 to −10.67), BMI (WMD -4.32 kg/m<sup>2</sup>, 95 % CI -4.75 to −3.89), and waist circumference (WMD -9.32 cm, 95 % CI -9.87 to −8.78). Semaglutide increased likelihood of achieving ≥5 % weight loss (RR 2.63, 95 % CI 2.12–3.25). Total adverse events were modestly but significantly elevated (RR 1.05, 95 % CI 1.01–1.09), primarily gastrointestinal symptoms. Serious adverse reactions were also higher (RR 1.33, 95 % CI 1.08–1.63).</div></div><div><h3>Conclusions</h3><div>Both oral and subcutaneous semaglutide significantly improve weight management in non-diabetic adults. While the safety profile is generally acceptable, elevated serious adverse events warrant careful patient selection and monitoring. Optimal outcomes occur with lifestyle interventions at doses ≥2.4 mg weekly.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178587"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.ejphar.2026.178586
Liangyu Chen , Xiaojun Liu , Ying Guo , Ying Liu , Xin Zheng , Shi Yin , Yifei Wang , Hui Xue , Jiamei Liu
Globally, traumatic brain injury (TBI) and stroke are the primary contributors to mortality and disability. In recent years, C-C chemokine receptor 5 (CCR5) has attracted much attention as a potential therapeutic target for stroke and TBI. Therefore, we performed a meta-analysis of animal models of stroke or TBI to assess the therapeutic effects of CCR5 inhibition. The PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), VIP Chinese Journal Service Platform (VIP), Ovid MEDLINE, Wanfang Data Knowledge Service Platform (Wanfang), and China Biomedical Literature Database (CBM) databases were searched, and twelve studies were included. The program Stata 17.0 was used to perform the statistical analysis. Overall, the results revealed that CCR5 inhibition reduced infarct volume, neurological deficit scores, and microglial activation and increased cAMP response element-binding protein (CREB) expression levels in animal models of stroke or TBI; however, there was no significant effect on astrocytes or the number of apoptotic cells. Subgroup analyses revealed that inhibition of CCR5 was more effective at reducing lesion volume in animal models of TBI, with CCR5 inhibitors, after the onset of stroke or TBI, and at intervention durations of 1–3 days. Furthermore, the results of this study suggest that the CCR5/PKA/CREB signaling pathway may be involved in the treatment of stroke and traumatic brain injury. These results suggest that CCR5 inhibition may have significant therapeutic uses in the management of TBI and stroke. However, further preclinical research is needed to assess the safety and effectiveness of CCR5 inhibitors with greater accuracy.
在全球范围内，创伤性脑损伤（TBI）和中风是导致死亡和残疾的主要原因。近年来，C-C趋化因子受体5 （CCR5）作为脑卒中和脑外伤的潜在治疗靶点备受关注。因此，我们对脑卒中或脑外伤动物模型进行了荟萃分析，以评估CCR5抑制的治疗效果。检索PubMed、Cochrane图书馆、Web of Science、中国知网（CNKI）、维普中文期刊服务平台（VIP）、Ovid MEDLINE、万方数据知识服务平台（Wanfang）、中国生物医学文献数据库（CBM）等数据库，共纳入12篇研究。采用Stata 17.0软件进行统计分析。总体而言，结果显示CCR5抑制减少脑卒中或TBI动物模型中的梗死体积、神经功能缺损评分和小胶质细胞激活，并增加cAMP反应元件结合蛋白（CREB）表达水平；但对星形胶质细胞及凋亡细胞数量无明显影响。亚组分析显示，CCR5抑制剂在脑卒中或TBI发病后，干预时间为1-3天，在TBI动物模型中，CCR5抑制剂在减少病变体积方面更有效。此外，本研究结果提示CCR5/PKA/CREB信号通路可能参与脑卒中和创伤性脑损伤的治疗。这些结果表明，CCR5抑制可能在TBI和卒中的治疗中具有重要的治疗作用。然而，需要进一步的临床前研究来更准确地评估CCR5抑制剂的安全性和有效性。
{"title":"The therapeutic effect of inhibition of CCR5 on animal models of stroke or traumatic brain injury: A systematic review and meta-analysis","authors":"Liangyu Chen , Xiaojun Liu , Ying Guo , Ying Liu , Xin Zheng , Shi Yin , Yifei Wang , Hui Xue , Jiamei Liu","doi":"10.1016/j.ejphar.2026.178586","DOIUrl":"10.1016/j.ejphar.2026.178586","url":null,"abstract":"<div><div>Globally, traumatic brain injury (TBI) and stroke are the primary contributors to mortality and disability. In recent years, C-C chemokine receptor 5 (CCR5) has attracted much attention as a potential therapeutic target for stroke and TBI. Therefore, we performed a meta-analysis of animal models of stroke or TBI to assess the therapeutic effects of CCR5 inhibition. The PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), VIP Chinese Journal Service Platform (VIP), Ovid MEDLINE, Wanfang Data Knowledge Service Platform (Wanfang), and China Biomedical Literature Database (CBM) databases were searched, and twelve studies were included. The program Stata 17.0 was used to perform the statistical analysis. Overall, the results revealed that CCR5 inhibition reduced infarct volume, neurological deficit scores, and microglial activation and increased cAMP response element-binding protein (CREB) expression levels in animal models of stroke or TBI; however, there was no significant effect on astrocytes or the number of apoptotic cells. Subgroup analyses revealed that inhibition of CCR5 was more effective at reducing lesion volume in animal models of TBI, with CCR5 inhibitors, after the onset of stroke or TBI, and at intervention durations of 1–3 days. Furthermore, the results of this study suggest that the CCR5/PKA/CREB signaling pathway may be involved in the treatment of stroke and traumatic brain injury. These results suggest that CCR5 inhibition may have significant therapeutic uses in the management of TBI and stroke. However, further preclinical research is needed to assess the safety and effectiveness of CCR5 inhibitors with greater accuracy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178586"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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