British Journal of Pharmacology最新文献

{"title":"Monovalent glycoconjugates of sulforaphane prevent inflammation induced by lipopolysaccharide in human dendritic cells by inhibiting NF-ĸB signalling pathway.","authors":"Camila Leiva-Castro, Ana Maria Múnera-Rodríguez, Macarena Martínez-Bailén, Ana Teresa Carmona, Soledad López-Enríquez, Francisca Palomares","doi":"10.1111/bph.70115","DOIUrl":"https://doi.org/10.1111/bph.70115","url":null,"abstract":"<p><strong>Background and purpose: </strong>Sulforaphane (SFN) has notable health benefits but faces challenges due to its poor solubility and delivery. This study investigates SFN-glycoconjugates effects on lipopolysaccharide (LPS)-induced inflammation in dendritic cells (DCs). With the aiming to enhance their therapeutic potential against inflammatory diseases. Novel monovalent SFN-glycoconjugates with mannose (Man) and fucose (0Fuc) were developed and tested for their anti-inflammatory and immune-modulatory properties in DCs from healthy donors under chronic LPS exposure.</p><p><strong>Experimental approach: </strong>By leveraging therapeutic strategies, SFN-glycoconjugates significantly improved the solubility and bioavailability of SFN, thereby overcoming the limitations of traditional delivery methods. Monocyte-derived DCs were treated with SFN-glycoconjugates and subsequently exposed to a chronic inflammatory environment induced by LPS.</p><p><strong>Key results: </strong>Our results showed that SFN-glycoconjugates enhance effectiveness in suppressing inflammation by targeting the p65 NF-κB pathway, without affecting MAPK signalling. SFN-glycoconjugates induce a tolerogenic immune response, characterized by increased IL-10 production and enhanced regulatory T- and B-cell proliferation. These effects surpass those of p65 NF-κB inhibition alone, highlighting a distinct and potent regulatory mechanism independent of MAPK pathways.</p><p><strong>Conclusion and implications: </strong>The integration of food therapeutic strategies not only enhances the stability and delivery of bioactive compounds but also broadens their potential applications in functional foods and therapeutic approaches. In particular, SFN-glycoconjugates represent a promising option as biologically active compounds for inflammatory diseases, offering enhanced anti-inflammatory and immunomodulatory effects through optimized delivery systems and the activation of specific molecular pathways.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the pathophysiology underlying clozapine-induced enhancement of glutamatergic transmission through L-glutamate and D-serine release associated with pannexin1 hemichannels.","authors":"Motohiro Okada, Ruri Okubo, Eishi Motomura","doi":"10.1111/bph.70112","DOIUrl":"https://doi.org/10.1111/bph.70112","url":null,"abstract":"<p><strong>Background and purpose: </strong>Clozapine, an approved antipsychotic for treatment-resistant schizophrenia (TRS), enhances glutamatergic transmission by increasing exocytosis and non-exocytosis glutamate release; however, its full action remained to be clarified.</p><p><strong>Experimental approach: </strong>This study determined the effects of chronic administration of clozapine on tripartite-synaptic glutamatergic transmission associated with N-methyl-D-aspartate (NMDA)/glutamate receptors (NMDARs) by using microdialysis, cultured astrocytes and capillary immunoblotting.</p><p><strong>Key results: </strong>Chronic clozapine administration dose- and time-dependently increased the basal release of L-glutamate and D-serine from astrocytes in the prefrontal cortex. A therapeutically relevant concentration of clozapine increased the expression of phosphorylated-Src, but not pannexin1, whereas a supratherapeutic concentration of clozapine increased the expression of both pannexin1 and phosphorylated-Src. Clozapine-induced increase of L-glutamate and D-serine release was inhibited by inhibitors of Src kinase and pannexin1 hemichannels, but not by inhibitors of NMDAR and connexin43-hemichannels. Clozapine enhanced synthesis of L-β-aminoisobutyrate (L-BAIBA) also increased astroglial release of L-glutamate and D-serine through pannexin1 hemichannels and increased expression of pannexin1 and phosphorylated Src. Activation of pannexin1-hemichannels by chronic administration of clozapine and L-BAIBA was regulated by Src kinase, which was inhibited by an inhibitor of group-III metabotropic glutamate receptors (III-mGluR). L-BAIBA enhances III-mGluR, although clozapine did not directly affect III-mGluR activity.</p><p><strong>Conclusions and implications: </strong>Enhanced glutamatergic transmission by chronic administration of therapeutically relevant concentrations of clozapine involves increased L-BAIBA signalling, which activates Src signalling via III-mGluR agonistic action, without affecting pannexin1 expression. Activation of pannexin1-hemichannel activity induced by Src signalling and III-mGluR may play an important role in the effectiveness of clozapine in TRS.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of the molecular mechanisms of drug-induced hidden cardiotoxicity by a multi-omics approach: The example of rofecoxib.","authors":"Bennet Y Weber, Gábor B Brenner, Barnabás Váradi, Bence Ágg, Csenger Kovácsházi, Olivér M Balogh, Donagh Egan, Kieran Wynne, David Matallanas, Rainer Schulz, Péter Ferdinandy, Zoltán Giricz, Anikó Görbe","doi":"10.1111/bph.70106","DOIUrl":"https://doi.org/10.1111/bph.70106","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hidden cardiotoxicity is defined as drug-induced cardiotoxicity that becomes obvious only in the presence of comorbidities. However, the molecular mechanisms of hidden cardiotoxicity are not always known. Therefore, unbiased multi-omics approaches could assist in revealing regulatory pathways. The most notable representative of hidden cardiotoxic drugs is the cyclooxygenase-2-inhibitor, rofecoxib. We previously reported increased mortality in rats because of proarrhythmic effects of rofecoxib in ischaemic hearts. Here, we aimed to identify molecular mechanisms of hidden cardiotoxicity exemplified by rofecoxib that present prior to comorbidities.</p><p><strong>Experimental approach: </strong>Rats were treated with rofecoxib or its vehicle for 4 weeks. RNA sequencing and proteomic datasets of heart samples were used for differential expression and pathway reconstruction analyses.</p><p><strong>Key results: </strong>In this model, mechanisms of hidden cardiotoxicity could not be revealed by transcriptomic analyses. However, mass-spectrometry-based proteomics showed conspicuous changes, revealing 132 proteins that were dysregulated in expression or on phosphorylation sites. Importantly, the phospho-proteomics allowed us to identify two kinases that may mediate cardiotoxicity. Finally, pathway reconstruction maps a complex molecular machinery whose clustered proteins regulate processes involving cytoskeleton binding, mRNA processing, proteolysis, translation, citrate acid cycle and calcium ion signalling.</p><p><strong>Conclusion and implications: </strong>This is the first demonstration that multi-omics characterisation can reveal underlying regulatory pathways of hidden cardiotoxicity. Importantly, our study shows that transcriptomics gives limited information on the hidden cardiotoxic effects of rofecoxib, which are mainly mediated by changes in posttranslational modifications and protein expression. These changes, among other mechanisms, may disturb the cardiac calcium handling, which could explain the fatal arrhythmias following ischaemia/reperfusion observed with rofecoxib.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optical control of calcium-permeable AMPA receptors by azobenzene-spermines.","authors":"Maxim Nikolaev, Elina Gataulina, Irina Fedorova, Nadezhda Baleeva, Mikhail Baranov, Alexander Vassilevski, Denis Tikhonov","doi":"10.1111/bph.70111","DOIUrl":"https://doi.org/10.1111/bph.70111","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury.","authors":"Inés Valencia, Andrea Pastor-Martínez, Céline Decouty-Pérez, Ana Belen Lopez-Rodriguez, María Álvarez-Rubal, Eva Ramos, Francesco Calzaferri, Jorge Zamorano-Fernández, Javier Giner-García, Alexis J Palpán-Flores, Víctor Rodríguez-Domínguez, Javier Rodríguez de Cía, Borja J Hernández-García, Alejandro Romero, Cristóbal de Los Ríos, Javier Egea","doi":"10.1111/bph.70108","DOIUrl":"https://doi.org/10.1111/bph.70108","url":null,"abstract":"<p><strong>Background and purpose: </strong>Traumatic brain injury (TBI) is considered to be a leading cause of mortality and disability worldwide. After TBI, innate immunity is rapidly activated in response to damage-associated molecular patterns, such as ATP release, recognised by P2X7 receptors. The P2X7-NLRP3 inflammasome axis has been identified as one of the main players in neuroinflammation. This study aimed to validate P2X7 receptors as therapeutic target for traumatic brain injury.</p><p><strong>Experimental approach: </strong>P2X7 receptors were studied by genetic and pharmacological approaches. Six non-nucleotide purine derivatives were evaluated as P2X7 antagonists. Compounds that prevented LPS + ATP-induced IL-1β release from primary glial cultures were investigated in the closed-head injury TBI model in vivo in male mice. Finally, we evaluated soluble (s)P2X7 receptor plasmatic levels in a cohort of TBI patients.</p><p><strong>Key results: </strong>P2rx7^-/- mice showed an exaggerated inflammatory response 24 h post-TBI compared to control mice. However, animals treated with the selective P2X7 antagonist JNJ-47965567 (30 mg kg^-1 i.p.) 30 min post-TBI showed improved neurological and inflammatory parameters. The purine derivative ITH15004 was the most potent compound reducing IL-1β production in vitro. When administered in vivo 30 min post-TBI, ITH15004 (1 mg kg^-1 i.p.) improved both neuro-behavioural and inflammatory markers at 24 h. In TBI patients, we showed a tendency towards increase in circulating sP2X7 receptor levels at 24 and 72 h post-TBI.</p><p><strong>Conclusions and implications: </strong>These results highlight the importance of P2X7 receptors in the acute phase of TBI and present ITH15004 as a promising pharmacological tool to counteract P2X7 receptor-dependent neuroinflammation in vivo.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galangin alleviates vitiligo by targeting ANXA2 degradation in macrophages.","authors":"Wenjing Wei, Abudureyimu Alimujiang, Zehua Zhang, Zulipikaer Wusiman, Xiangran Liu, Yong Zhu, Yipeng Bai, Ziqi Zhu, Zhijian Li, Dengqiu Xu, Shixia Huo","doi":"10.1111/bph.70103","DOIUrl":"https://doi.org/10.1111/bph.70103","url":null,"abstract":"<p><strong>Background and purpose: </strong>Vitiligo, a common depigmenting skin disorder, is characterised by the selective loss of melanocytes, which leads to distinctive non-scaly, chalky-white macules. Galangin is a flavonoid found in galangal and propolis; our previous study highlighted the therapeutic potential of galangin. However, the contributions of galangin to restoring skin pigmentation and maintaining immune homeostasis, as well as its detailed molecular roles in vitiligo management, have not been fully elucidated.</p><p><strong>Experimental approach: </strong>We used C57BL/6J mice with H₂O₂-induced vitiligo or imiquimod-induced erythema, to test the anti-vitiligo effects and anti-inflammatory effects of galangin. Other techniques used included immunoprecipitation-mass spectrometry, pull-down assays, Autodock and surface plasmon resonance (SPR) analysis in cultured cells.</p><p><strong>Key results: </strong>Galangin exerted anti-inflammatory and antioxidant effects through two mechanisms, promoting melanocyte proliferation while inhibiting macrophage proliferation. Using immunoprecipitation-mass spectrometry, pull-down assays, Autodock and SPR analyses, we found that galangin bound to annexin A2 and promoted its degradation in macrophages. This interaction led to inhibition of macrophage proliferation, activation and polarisation. In vivo, galangin significantly improved skin conditions in mice with H₂O₂-induced vitiligo or imiquimod-induced erythema. Furthermore, annexin A2 knockout abolished the protective effects of galangin in these models.</p><p><strong>Conclusions and implications: </strong>Galangin bound to annexin A2 and promoted its degradation in macrophages, decreasing release of inflammatory factors and chemokines. These findings provide experimental evidence supporting the potential application of galangin in clinical treatments for vitiligo and highlight ANXA2 as a promising therapeutic target for managing this condition.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polypharmacy in mice disrupts left ventricular function and structure and promotes proteome reorganisation in an age- and sex-specific fashion.","authors":"Trang Tran, Kevin Winardi, Scott P Levick, Alexander Widiapradja, Gizem Gemikonakli, Susan E Howlett, Matthew J McKay, Mark P Molloy, John Mach, Sarah N Hilmer","doi":"10.1111/bph.70082","DOIUrl":"https://doi.org/10.1111/bph.70082","url":null,"abstract":"<p><strong>Background and purpose: </strong>Most older people use polypharmacy (≥5 medications), particularly those with cardiovascular disease. The effects of polypharmacy on the cardiovascular system are not well described. We examined the effect of a chronic polypharmacy regimen on left ventricular (LV) function, structure and proteome in young and old mice of both sexes.</p><p><strong>Experimental approach: </strong>Young (4 months) and old (23 months) C57BL/6JArc male and female mice were treated with an oral polypharmacy regimen (therapeutic doses of oxybutynin, oxycodone, citalopram, simvastatin and metoprolol) or control. Blood pressure and echocardiography were assessed after 4 and 9 weeks of treatment, respectively. After 10 weeks of treatment, LV histology and proteome was assessed.</p><p><strong>Key results: </strong>Polypharmacy reduced heart rate in all groups, whereas its effect on LV structure varied by age and sex. Relative LV wall thickness increased, and LV diameter decreased with polypharmacy in older males, consistent with concentric hypertrophy. The LV proteome showed dysregulation in structural proteins, calcium handling proteins, metabolic enzymes and antioxidants. When comparing polypharmacy against age- and sex-matched controls, 195 unique differentially expressed proteins were identified, most in old males (141 proteins). Co-expression network analysis linked LV structural changes with expression of proteins involved in protein folding and trafficking and linked heart rate effects with desmosomal protein expression.</p><p><strong>Conclusions and implications: </strong>These findings suggest that, in mice, polypharmacy affected cardiac function and structure differently depending upon age and sex, with older males being the most affected. Further investigation may elucidate mechanisms and inform personalised medicine.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychedelics, entactogens and psychoplastogens for depression and related disorders.","authors":"Daniel Hoyer","doi":"10.1111/bph.70088","DOIUrl":"https://doi.org/10.1111/bph.70088","url":null,"abstract":"<p><p>Currently, the most actively investigated rapidly acting antidepressants, anxiolytics and/or anti PTSD agents, include psychedelics e.g. psilocybin, LSD, N,N-dimethyltryptamine, ayahuasca; non-hallucinogenic entactogens, e.g. MDMA; psychoplastogens which rapidly promote neuroplasticity, e.g. ibogaine, ketamine and esketamine; and other atypicals e.g. dextromorphan/bupropion, esmethadone. Late-stage clinical trials support psychedelics and/or MDMA-assisted psychotherapy as rapidly acting treatments for major depressive disorder (MDD), treatment-resistant depression (TRD), PTSD or generalised anxiety disorders (GAD). Psilocybin, MDMA and LSD were granted FDA breakthrough status for TRD/MDD, PTSD and GAD, respectively, although FDA recently rejected the new drug application of MDMA in PTSD. Most of these drugs target the 5-HT and monoamine systems. Classical psychedelics act as 5-HT_2A receptor agonists, although LSD, DMT and psilocybin target other 5-HT and/or dopamine receptors. Psychedelic-dependent 5-HT_2A receptor agonism also has profound anti-(neuro)inflammatory effects. Advanced imaging studies suggest that brain 5-HT levels are reduced in depression. Functional magnetic resonance studies show that neural networks (cortico thalamic, salience, default mode) are profoundly impaired in depression. Such network defects are corrected upon psychedelic/entactogen treatment, offering a unique opportunity to serve as biomarkers for depression, anxiety and PTSD precision medicine trials. Psychedelics and entactogens target common end pathways, namely neuroplasticity/synaptogenesis, either directly via monoamine or glutamate receptors and/or indirectly, via BDNF and mTORC1 pathways. Together, these findings strongly support a biological basis for MDD, GAD, PTSD and related conditions, which can be considered as mixed biochemical, neurological and neuroimmune disorders, and are profoundly modified by psychedelics, entactogens and the newly developed psychoplastogens.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining the polycystin pharmacophore through high-throughput screening and computational biophysics.","authors":"Eduardo Guadarrama, Carlos G Vanoye, Paul G DeCaen","doi":"10.1111/bph.70080","DOIUrl":"10.1111/bph.70080","url":null,"abstract":"<p><strong>Background and purpose: </strong>Polycystins (PKD2, PKD2L1) are voltage-gated and Ca²⁺-modulated members of the TRP family of ion channels. Loss of PKD2L1 results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 cause autosomal dominant polycystic kidney disease. Despite decades of evidence demonstrating their physiological importance in the brain and kidneys and linking their dysfunction to human disease, the polycystin pharmacophore remains undefined. Contributing to this knowledge gap is their resistance to drug screening campaigns, which are hindered by the unique subcellular trafficking of these channels to organelles such as the primary cilium. PKD2L1 is the only member of the polycystin family to form constitutively active ion channels in the plasma membrane when overexpressed.</p><p><strong>Experimental approach: </strong>HEK293 cells stably expressing PKD2L1 F514A were screened pharmacologically via high-throughput electrophysiology to identify potent polycystin channel modulators. In silico docking analysis and mutagenesis were used to define the receptor sites of screen hits. Inhibition by membrane-impermeable QX-314 was used to evaluate PKD2L1-binding site accessibility.</p><p><strong>Key results: </strong>Screen results identify potent PKD2L1 inhibitors with divergent chemical core structures and highlight striking similarities between the molecular pharmacology of PKD2L1 and voltage-gated sodium channels. Docking analysis, channel mutagenesis and electrophysiological recordings identify an open-state accessible lateral fenestration receptor within the pore and a mechanism of inhibition that stabilises the PKD2L1 inactivated state.</p><p><strong>Conclusions and implications: </strong>Outcomes establish the suitability of our approach to expand our chemical knowledge of polycystins and delineate novel receptor moieties for the development of channel-specific inhibitors in TRP channel research.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPCR-G protein signalling and its mutational landscape in cancer-Driver or passenger.","authors":"Chenlin Feng, Jasper F Ooms, Erik H J Danen, Laura H Heitman","doi":"10.1111/bph.70102","DOIUrl":"https://doi.org/10.1111/bph.70102","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) play a crucial role in cellular signalling, regulating various physiological processes. Abnormal expression and mutations of GPCRs have been implicated in several types of cancer, influencing tumour initiation, progression and immune response. In this review, we present an overview of recent research on GPCR involvement in cancer and discuss the evidence supporting whether mutations in GPCRs act as cancer driver or passenger. Accumulation of GPCR mutations in some highly conserved structural motifs and the mutually exclusiveness observed between G_i-coupled GPCRs and G protein subunit alpha S (GNAS)-activating mutations indicate their potential driving role in cancer. However, the functional redundancy of GPCR signalling networks together with the widespread but low frequency distribution of GPCR mutations indicate that they may rather act as passengers. The future of GPCR drug discovery hinges on overcoming challenges related to data availability and the integration of GPCR research with broader cancer studies using multiomics approaches.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}