Pharmacology & Therapeutics最新文献

{"title":"Receptor dimers and biased ligands: Novel strategies for targeting G protein-coupled receptors","authors":"Wenkai Liu ,&nbsp;Dexiu Wang ,&nbsp;Luoqi Wang ,&nbsp;Shujuan Hu ,&nbsp;Yunlu Jiang ,&nbsp;Yixiang Wang ,&nbsp;Xin Cai ,&nbsp;Jing Chen","doi":"10.1016/j.pharmthera.2025.108829","DOIUrl":"10.1016/j.pharmthera.2025.108829","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are the largest superfamily of membrane receptors. They regulate physiological and pathological processes such as metabolic homeostasis, cell proliferation and differentiation, and the immune response, and are one of the most important classes of drug targets, being targeted by 30–40 % of marketed drugs. A growing number of studies continue to reveal the complexity of GPCRs, especially their ability to interact with each other to form higher-order structures such as homodimers and heterodimers, which have different functions than monomers, and are involved in disease development and progression. The existence of GPCR homodimers and heterodimers is opening up new directions in drug discovery and development to harness their therapeutic potential. Particularly striking is the ability of GPCR dimers to trigger unique biased signalling pathways, which exquisitely balance the relationship between therapeutic effects and side effects. By suppressing adverse reactions and enhancing beneficial drug effects, GPCR dimers provide an unprecedented opportunity to minimise side effects, maximise therapeutic efficacy and enhance safety. This review aims to highlight the latest research advances in GPCR dimerization and GPCR-biased signalling, focusing on the development of dimer-targeting and biased ligands as innovative drugs that will likely provide new strategies for treating GPCR-related diseases as well as a better understanding of drug design for compounds that target GPCRs. GPCRs will play an increasingly important role in precision medicine and personalised therapy, leading us towards a safer, more efficient and smarter pharmaceutical future.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108829"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G protein-coupled estrogen receptor biased signaling in health and disease","authors":"Aisha Bushi ,&nbsp;Yixuan Ma ,&nbsp;Joseph Adu-Amankwaah ,&nbsp;Rong Wang ,&nbsp;Fen Cui ,&nbsp;Rui Xiao ,&nbsp;Jinming Zhao ,&nbsp;Jinxiang Yuan ,&nbsp;Rubin Tan","doi":"10.1016/j.pharmthera.2025.108822","DOIUrl":"10.1016/j.pharmthera.2025.108822","url":null,"abstract":"<div><div>G protein-coupled estrogen receptor (GPER) is now recognized for its pivotal role in cellular signaling, influencing diverse physiological processes and disease states. Unlike classical estrogen receptors, GPER exhibits biased signaling, wherein ligand binding triggers selective pathways over others, significantly impacting cellular responses. This review explores the nuanced mechanisms of biased signaling mediated by GPER, underscoring its relevance in cardiovascular health, neurological function, immune modulation, and oncogenic processes. Despite its critical implications, biased signaling through GPER remains underexplored compared to traditional signaling paradigms. We explore recent progress in understanding GPER signaling specificity and its potential therapeutic implications across various diseases. Future research directions aim to uncover the molecular basis of biased signaling, develop selective ligands, and translate these insights into personalized therapeutic approaches. Exploiting the therapeutic potential of GPER biased signaling represents a promising frontier in precision medicine, offering innovative strategies to address unmet medical needs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108822"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of macrophages in asthma-related fibrosis and remodelling","authors":"Xin Yuan Yang ,&nbsp;Fuguang Li ,&nbsp;Guojun Zhang ,&nbsp;Paul S. Foster ,&nbsp;Ming Yang","doi":"10.1016/j.pharmthera.2025.108820","DOIUrl":"10.1016/j.pharmthera.2025.108820","url":null,"abstract":"<div><div>Airway remodelling significantly contributes to the progressive loss of lung function and heightened symptom severity in chronic asthma. Additionally, it often persists and demonstrates reduced responsiveness to the mainstay treatments. The excessive deposition of collagen and extracellular matrix proteins leads to subepithelial fibrosis and airway remodelling, resulting in increased stiffness and decreased elasticity in the airway. Studies have emphasized the crucial role of subepithelial fibrosis in the pathogenesis of asthma. Fibrotic processes eventually cause airway narrowing, reduced lung function, and exacerbation of asthma symptoms. Macrophages play a crucial role in this process by producing pro-fibrotic cytokines, growth factors, and enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Additionally, identification of novel genetic markers has provided evidence for a strong genetic component in fibrosis within macrophage regulated fibrosis. Although macrophages contribute to the progression of airway remodelling and subepithelial fibrosis, interventions targeting macrophage-driven fibrotic changes have not yet been developed. This review synthesizes research on the intricate pathways through which macrophages contribute to subepithelial fibrosis in chronic asthma and its' pathological features. Understanding the interplay between macrophages, fibrosis, and asthma pathogenesis is essential for developing effective therapeutic strategies to manage severe asthma and improve patient outcomes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108820"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472117","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":"Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets","authors":"Yi Chu,&nbsp;Su Yang,&nbsp;Xiaodong Chen","doi":"10.1016/j.pharmthera.2025.108844","DOIUrl":"10.1016/j.pharmthera.2025.108844","url":null,"abstract":"<div><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1–4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108844"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory bowel disease and neuropsychiatric disorders: Mechanisms and emerging therapeutics targeting the microbiota-gut-brain axis","authors":"Giulia Petracco ,&nbsp;Isabella Faimann ,&nbsp;Florian Reichmann","doi":"10.1016/j.pharmthera.2025.108831","DOIUrl":"10.1016/j.pharmthera.2025.108831","url":null,"abstract":"<div><div>Crohn's disease (CD) and ulcerative colitis (UC) are the two major entities of inflammatory bowel disease (IBD). These disorders are known for their relapsing disease course and severe gastrointestinal symptoms including pain, diarrhoea and bloody stool. Accumulating evidence suggests that IBD is not only restricted to the gastrointestinal tract and that disease processes are able to reach distant organs including the brain. In fact, up to 35 % of IBD patients also suffer from neuropsychiatric disorders such as generalized anxiety disorder and major depressive disorder. Emerging research in this area indicates that in many cases these neuropsychiatric disorders are a secondary condition as a consequence of the disturbed communication between the gut and the brain via the microbiota-gut-brain axis. In this review, we summarise the current knowledge on IBD-associated neuropsychiatric disorders. We examine the role of different pathways of the microbiota-gut-brain axis in the development of CNS disorders highlighting altered neural, immunological, humoral and microbial communication. Finally, we discuss emerging therapies targeting the microbiota-gut-brain axis to alleviate IBD and neuropsychiatric symptoms including faecal microbiota transplantation, psychobiotics, microbial metabolites and vagus nerve stimulation.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108831"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536356","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":"Biased agonism in peptide-GPCRs: A structural perspective","authors":"Tharindunee Jayakody ,&nbsp;Dinath Kavishka Budagoda ,&nbsp;Krishan Mendis ,&nbsp;Withanage Dhanuka Dilshan ,&nbsp;Duvindu Bethmage ,&nbsp;Rashmi Dissasekara ,&nbsp;Gavin Stewart Dawe","doi":"10.1016/j.pharmthera.2025.108806","DOIUrl":"10.1016/j.pharmthera.2025.108806","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are dynamic membrane receptors that transduce extracellular signals to the cell interior by forming a ligand–receptor-effector (ternary) complex that functions via allosterism. Peptides constitute an important class of ligands that interact with their cognate GPCRs (peptide-GPCRs) to form the ternary complex. “Biased agonism”, a therapeutically relevant phenomenon exhibited by GPCRs owing to their allosteric nature, has also been observed in peptide-GPCRs, leading to the development of selective therapeutics with fewer side effects. In this review, we have focused on the structural basis of signalling bias at peptide-GPCRs of classes A and B, and reviewed the therapeutic relevance of bias at peptide-GPCRs, with the hope of contributing to the discovery of novel biased peptide drugs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108806"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073016","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":"The anti-inflammatory effects of saponins from natural herbs","authors":"Qinpin Zheng ,&nbsp;Tian Wang ,&nbsp;Sensen Wang ,&nbsp;Zhuoxi Chen ,&nbsp;Xue Jia ,&nbsp;Hui Yang ,&nbsp;Huijin Chen ,&nbsp;Xin Sun ,&nbsp;Kejun Wang ,&nbsp;Leiming Zhang ,&nbsp;Fenghua Fu","doi":"10.1016/j.pharmthera.2025.108827","DOIUrl":"10.1016/j.pharmthera.2025.108827","url":null,"abstract":"<div><div>Inflammation is a protective mechanism that also starts the healing process. However, inflammatory reaction may cause severe tissue damage. The increased influx of phagocytic leukocytes may produce excessive amount of reactive oxygen species, which leads to additional cell injury. Inflammatory response activates the leukocytes and thus induces tissue damage and prolongs inflammation. The inflammation-induced activation of the complement system may also contribute to cell injury. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are chief agents for treating inflammation associated with the diseases. However, the unwanted side effects of NSAIDs (<em>e.g.</em>, gastrointestinal disturbances, skin reactions, adverse renal effects, cardiovascular side effects) and glucocorticoids (<em>e.g.</em>, suppression of immune system, Cushing's syndrome, osteoporosis, hyperglycemia) limit their use in patients. Natural herbs are important sources of anti-inflammatory drugs. The ingredients extracted from natural herbs display anti-inflammatory effects to work through multiple pathways with lower risk of adverse reaction. At present, the main anti-inflammatory natural agents include saponins, flavonoids, alkaloids, polysaccharides, and so on. The present article will review the anti-inflammatory effects of saponins including escin, ginsenosides, glycyrrhizin, astragaloside, Panax notoginseng saponins, saikosaponin, platycodin, timosaponin, ophiopogonin D, dioscin, senegenin.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108827"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders?","authors":"Abdelilah Arredouani","doi":"10.1016/j.pharmthera.2025.108824","DOIUrl":"10.1016/j.pharmthera.2025.108824","url":null,"abstract":"<div><div>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity—conditions for which they have received widespread approval—but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD).</div><div>Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns—particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis—emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD.</div><div>The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise.</div><div>This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as “magic drug” therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108824"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The (neuro)inflammatory system in anxiety disorders and PTSD: Potential treatment targets","authors":"Anupam Sah,&nbsp;Nicolas Singewald","doi":"10.1016/j.pharmthera.2025.108825","DOIUrl":"10.1016/j.pharmthera.2025.108825","url":null,"abstract":"<div><div>Targeting the immune system has recently garnered attention in the treatment of stress- associated psychiatric disorders resistant to existing pharmacotherapeutics. While such approaches have been studied in considerable detail in depression, the role of (neuro)inflammation in anxiety-related disorders, or in anxiety as an important transdiagnostic symptom, is much less clear. In this review we first critically review clinical and in part preclinical evidence of central and peripheral immune dysregulation in anxiety disorders and post-traumatic stress disorder (PTSD) and briefly discuss proposed mechanisms of how inflammation can affect anxiety-related symptoms. We then give an overview of existing and potential future targets in inflammation-associated signal transduction pathways and discuss effects of different immune-modulatory drugs in anxiety-related disorders. Finally, we discuss key gaps in current clinical trials such as the lack of prospective studies involving anxiety patient stratification strategies based on inflammatory biomarkers. Overall, although evidence is rather limited so far, there is data to indicate that increased (neuro)inflammation is present in subgroups of anxiety disorder patients. Although exact identification of such immune subtypes of anxiety disorders and PTSD is still challenging, these patients will likely particularly benefit from therapeutic targeting of aspects of the inflammatory system. Different anti-inflammatory treatment approaches (microglia-directed treatments, pro-inflammatory cytokine inhibitors, COX-inhibitors, phytochemicals and a number of novel anti-inflammatory agents) have indeed shown some efficacy even in non-stratified anxiety patient groups and appear promising as novel alternative or complimentary therapeutic options in specific (“inflammatory”) subtypes of anxiety disorder and PTSD patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108825"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471990","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":"Biased signaling in drug discovery and precision medicine","authors":"Ren-Lei Ji,&nbsp;Ya-Xiong Tao","doi":"10.1016/j.pharmthera.2025.108804","DOIUrl":"10.1016/j.pharmthera.2025.108804","url":null,"abstract":"<div><div>Receptors are crucial for converting chemical and environmental signals into cellular responses, making them prime targets in drug discovery, with about 70% of drugs targeting these receptors. Biased signaling, or functional selectivity, has revolutionized drug development by enabling precise modulation of receptor signaling pathways. This concept is more firmly established in G protein-coupled receptor and has now been applied to other receptor types, including ion channels, receptor tyrosine kinases, and nuclear receptors. Advances in structural biology have further refined our understanding of biased signaling. This targeted approach enhances therapeutic efficacy and potentially reduces side effects. Numerous biased drugs have been developed and approved as therapeutics to treat various diseases, demonstrating their significant therapeutic potential. This review provides a comprehensive overview of biased signaling in drug discovery and disease treatment, highlighting recent advancements and exploring the therapeutic potential of these innovative modulators across various diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"268 ","pages":"Article 108804"},"PeriodicalIF":12.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}