Pharmacological Reviews最新文献

{"title":"Application of human liver cell models in drug development and toxicity studies: The role of membrane transporters.","authors":"Edit Szabó, Ágnes Telbisz, Zsuzsa Erdei, Kiara Gitta Farkas, László Homolya, Balázs Sarkadi, Ágota Apáti","doi":"10.1016/j.pharmr.2026.100157","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100157","url":null,"abstract":"<p><p>The critical involvement of hepatic transporters in both physiological and pathological processes, including metabolic diseases, drug metabolism, and toxicity, represents a key issue in pharmacology. The expression and localization of transporters involved in hepatic functions are especially important in new drug development and toxicology studies. Because of major species differences in transporter expression, localization, and substrate recognition, the value of animal experiments is limited in this regard, and human liver cell preparations are already available to allow relevant in vitro studies. Currently, the gold standard for in vitro studies is the primary human liver cell preparation. However, the interindividual heterogeneity, low reproducibility, and high price of such preparations are prohibiting their widespread use. Hepatocytes derived from liver tumors are widely used in toxicology studies, but each of these cell lines has specific advantages and shortcomings. Stem cell-based liver cell preparations, especially spheroids and organoids derived from human induced pluripotent stem cells, may serve as a new toolbox for studying a variety of membrane transporters and complex metabolic interactions in human hepatocytes. These advanced preparations, although currently somewhat premature, should provide an excellent basis for comprehensive in vitro functional assays. The present paper provides a comparative review of our current understanding of the pharmacological relevance of hepatic transporters, their interactions with the key players of general drug metabolism, their complex regulation, as well as the recent methodologies to apply human-relevant in vitro systems in drug development and toxicology studies. SIGNIFICANCE STATEMENT: This review addresses the critical need for advanced human liver models in drug development, moving away from animal testing and inadequate tumor-derived cells. By evaluating emerging stem cell-derived 2D and 3D cultures, it highlights the often-overlooked role of membrane transporters-crucial for understanding how drugs enter and exit cells. This work provides a roadmap for creating physiologically accurate models to better predict drug safety, efficacy, and toxicity in humans.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 6","pages":"100157"},"PeriodicalIF":20.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945497","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":"Recombinant protein drug metabolism and pharmacokinetics.","authors":"Jie-Bing Jiang, Huan-Yu Zhao, Zhu-Wei Miao, Chao-Yu Miao","doi":"10.1016/j.pharmr.2026.100155","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100155","url":null,"abstract":"<p><p>Recombinant proteins represent a critically important class of biopharmaceuticals and are indispensable for the prevention and treatment of various clinical diseases. However, their in vivo disposal is far more complex than those of small-molecule drugs. Unfortunately, pharmacokinetic (PK) studies of recombinant proteins still lag far behind those of small molecules, and most investigations are limited to the determination of overall PK parameters, with insufficient exploration at the cellular and subcellular levels or in-depth mechanistic insights. Inadequate understanding of the PK and metabolic characteristics of recombinant proteins frequently leads to limited or diminished efficacy and suboptimal safety profiles in clinical practice. Moreover, with the emergence of a growing number of novel recombinant proteins in recent years, such as monoclonal antibodies and fusion proteins, the PK research of recombinant proteins has become increasingly extensive while also facing mounting new challenges. Therefore, this article focuses on the PKs and metabolic characteristics of both classical and novel recombinant proteins, as well as the factors affecting their in vivo disposal, in order to enhance their therapeutic efficacy and safety through optimization of their PKs. To our knowledge, no comprehensive review has systematically summarized the PK properties and metabolic mechanisms of recombinant proteins, which highlights the necessity of this review. Furthermore, mechanistic insights into the PKs of recombinant proteins, particularly their metabolic mechanisms, remain scarce and outdated. We hope this review can draw more attention to this vital yet understudied area and promote further in-depth exploration. SIGNIFICANCE STATEMENT: Recombinant proteins, as indispensable clinical therapeutic agents, face limitations in achieving better efficacy and safety due to insufficient understanding of their PKs. This systematic review elucidates the PKs and metabolic mechanisms of recombinant proteins in the body, along with associated influencing factors. The information provided herein aims to deepen the understanding of the PK properties and disposal mechanisms of recombinant proteins, thus maximizing their potential clinical values in disease prevention and treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 6","pages":"100155"},"PeriodicalIF":20.3,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017460","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 skeletal connectome: From molecular circuitry to systemic network medicine.","authors":"Wenqiang Liu, Dong Liu, Qianqian Liu, Yang Sun","doi":"10.1016/j.pharmr.2026.100154","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100154","url":null,"abstract":"<p><p>Although classically viewed as a mechanical scaffold, the skeleton is increasingly recognized as a dynamic endocrine and sensory hub that integrates systemic biophysical and biochemical cues. In this review, we rethink skeletal physiology by proposing the 'skeletal connectome,' a network medicine framework that links circuit-level remodeling programs to multiorgan homeostasis. Structurally, we first distill the cellular logic of bone remodeling, emphasizing how osteoblasts, osteoclasts, and osteocytes act as plastic network nodes whose state transitions are constrained by topology, compartmentalization, and metabolic/biophysical gating. We subsequently map macroscopic connectome architecture, detailing bidirectional axes coupling bone to the immune, metabolic, neural, and muscular systems. Within this framework, we systematically re-evaluate diverse skeletal disorders, spanning mechanometabolic degeneration, autoimmune disease, endocrine-metabolic fragility, and bone metastasis. We conceptualize these conditions as resulting from specific disruptions in systemic communication networks. From a translational perspective, this connectome paradigm guides the evaluation of precision therapeutics, such as targeted protein degradation and mRNA-based drugs, designed to rewire dysfunctional circuits. Finally, we discuss emerging concepts like digital skeletal twins and in silico clinical trials, highlighting their promising conceptual/translational status-rather than as established clinical tools-to eventually complement real-world evidence in future personalized regimen design. SIGNIFICANCE STATEMENT: This review proposes the 'skeletal connectome' framework, redefining bone as a dynamic sensory and endocrine hub that integrates mechanical, metabolic, and immune circuits to sustain systemic homeostasis. By mapping diverse pathologies as characteristic network failure modes rather than isolated defects, this study outlines a translational roadmap for rewiring dysfunctional circuitry through precision perturbations-including mRNA therapeutics and targeted protein degradation-guided by digital skeletal twins.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 6","pages":"100154"},"PeriodicalIF":20.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945475","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":"Kv7 channels as pharmacological targets for central nervous system diseases.","authors":"Francesco Miceli, Maria Virginia Soldovieri, Vincenzo Barrese, Maurizio Taglialatela","doi":"10.1016/j.pharmr.2026.100153","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100153","url":null,"abstract":"<p><p>Neuronal Kv7 (also known as KCNQ) voltage-gated potassium channels are key regulators of membrane excitability, primarily through their contribution to the M-current, a slowly activating and noninactivating potassium conductance that stabilizes the resting membrane potential and limits repetitive firing. Given the central role of the M-current in regulating critical central nervous system functions, it is not surprising that Kv7 channel dysfunction contributes to the onset and progression of a wide range of neuropsychiatric disorders, and that Kv7 channels are primary targets for pharmacological intervention in all these conditions. In this review, we provide a comprehensive overview of the physiological roles of neuronal Kv7 subunits (Kv7.2-Kv7.5) with particular emphasis on their expression patterns during development and across distinct neuronal populations. We also discuss the complex regulatory mechanisms governing Kv7 channel expression, trafficking, and function, including modulation by intracellular signaling pathways and interacting proteins. Particular attention is devoted to the involvement of Kv7 channel dysfunction in epileptic encephalopathies, pain syndromes, and neuropsychiatric conditions, as well as neurodegenerative disorders such as Alzheimer and Parkinson disease, where altered neuronal excitability is a common pathogenic hallmark. Furthermore, we examine the evolving pharmacological landscape of Kv7 channel modulators, from first-generation openers such as retigabine to next-generation agents, repurposed drugs, natural products, and Kv7 modulators currently in clinical development, highlighting both their therapeutic promise and existing challenges. Collectively, available evidence identifies Kv7 channels as versatile and highly attractive pharmacological targets for the treatment of central nervous system disorders characterized by maladaptive changes in neuronal excitability. SIGNIFICANCE STATEMENT: Kv7 channels are central regulators of neuronal excitability and are increasingly recognized as key therapeutic targets in multiple central nervous system disorders. Advancing our understanding of their pathophysiological role may enable the development of more selective and effective treatments for diseases driven by maladaptive changes in neuronal excitability.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 6","pages":"100153"},"PeriodicalIF":20.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025795","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":"Erratum to \"Links between COVID-19, long COVID, and neurodegeneration: The role of glycosphingolipids\" [Pharmacological Reviews 78 (2026) 100113].","authors":"Michael Spedding, Johannes Aerts, Steve Alexander, Aurélie-Gaëlle Bellozzi Woestelandt, Elena Chiricozzi, Alexandre Henriques, Pierre-Marie Lledo, Jean-Philippe Loeffler, Rushika Perera, Frances M Platt, Pierre-François Pradat, Frédérique Rene, Anthony Schapira, Laura St Clair, Kevin Talbot, Maxime Taquet, Michal Toborek, Bradley Turner, Michael Zandi, Pierre Gressens","doi":"10.1016/j.pharmr.2026.100142","DOIUrl":"10.1016/j.pharmr.2026.100142","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100142"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147983088","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":"Mitochondrial metabolism as a pharmacological target for cancer therapeutics.","authors":"Yiran Yu, Wenwen Ding, Shihua Liu, Christophe Glorieux, Panpan Liu, Peng Huang","doi":"10.1016/j.pharmr.2026.100137","DOIUrl":"10.1016/j.pharmr.2026.100137","url":null,"abstract":"<p><p>Mitochondria are essential cellular organelles that were first identified in the mid-19th century. Despite more than 150 years of research and the accumulation of vast wealth of knowledge on mitochondrial structure and functions, new breakthroughs are still being made in recent years in key areas of mitochondrial biology. In the field of cancer research, major progress includes the elucidation of the role of mitochondria in cancer metabolic reprogramming, the discovery of signaling pathways in the crosstalk between mitochondria and the nucleus, the revelation of significant mitochondrial impact on tumor microenvironment and immune cells, the realization of the intriguing interplay between gut microbiota and cancer metabolism, the identification of molecular targets in mitochondria and the related pathways, and the development of mitochondria-targeted drugs such as mitocans for cancer treatment. This new progress underscores the essential role of mitochondria as multifaceted regulators of cancer metabolism, signal transduction, and cell survival, and as key pharmacological targets. This article will provide an up-to-date review of these important areas. The implications of these new research advances in cancer pharmacology and therapeutics will be explored, and interesting concepts that provide alternative theories for bioenergetics will also be discussed. SIGNIFICANCE STATEMENT: As a central hub for cellular energy production and biomolecule metabolism, mitochondria play essential roles in regulating metabolic and redox homeostasis, significantly affecting cell proliferation, survival, and sensitivity to pharmacological agents. Dysfunction of mitochondria in cancer cells alters these vital processes and affects tumor growth and therapeutic responses. Thus, a comprehensive understanding of mitochondrial alterations, the underlying regulatory mechanisms, and their impacts on pharmacological targets is pivotal for developing more effective therapeutic agents with significant clinical implications in cancer treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100137"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055116","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":"Pharmacogenomics of antibacterial and antiviral therapies: Clinical actionability, evidence gaps, and future directions.","authors":"Maria K Smatti, Zainab Jan, Hadi M Yassine","doi":"10.1016/j.pharmr.2026.100136","DOIUrl":"10.1016/j.pharmr.2026.100136","url":null,"abstract":"<p><p>Anti-infective drugs have profoundly transformed the history of medicine. Yet, with the presence of approximately 4.1-5 million interindividual genomic variants in human genome, patients are expected not to respond equally to the same anti-infective drug. This genetic variability, together with nongenetic factors, influences therapeutic outcomes and contributes to drug-induced adverse events in predisposed individuals. Historically, the identification of HLA-B∗57:01 as a predictor of abacavir hypersensitivity in patients with HIV represented the first successful clinical application of pharmacogenomics (PGx) in infectious diseases. Since then, the field has continued to evolve, as evidenced by the discovery of multiple clinically relevant gene-drug pairs, primarily related to immune responses, drug metabolism, and drug transport pathways. The evidence accumulated to date has established a number of mandatory (HLA-B∗57:01-abacavir) and actionable (MT-RNR1-aminoglycosides, CYP2B6-efavirenz, G6PD-nitrofurantoin, G6PD-nalidixic acid, and G6PD-dapsone) gene-drug pairs, whereas most other associations remain informative or exploratory without current guideline-based prescribing recommendations. Despite this progress, robust PGx evidence remains predominantly focused on antiretrovirals, anti-hepatitis C virus, and selected antimicrobial drug classes, such as β-lactams, aminoglycosides, sulfonamides, and antituberculosis drugs. For many other anti-infective agents, current evidence suggests that host genetic variation may have a limited impact on drug efficacy or safety, or that existing studies remain insufficiently powered or replicated to support clinical translation. The narrow ancestral diversity in PGx studies and clinical trials has also restricted the breadth of the knowledge gained and, consequently, the development of inclusive guidelines. This review summarizes the current PGx landscape of antibacterial and antiviral drugs and highlights key challenges and opportunities to improve clinical actionability. Greater inclusion of previously underrepresented populations, coupled with integrative multiomics approaches powered by artificial intelligence and machine learning, could accelerate PGx biomarker identification, validation, and integration into personalized patient care. SIGNIFICANCE STATEMENT: Rapid and effective deployment of anti-infective drugs requires incorporating knowledge of host genetic determinants of drug effectiveness or adverse events, the latter of which is a leading cause of death. The evolution of data science, driven by available genomic data, represents an unprecedented opportunity to accelerate pharmacogenomics discovery in infectious diseases. If acquired at a population level and integrated into medical records, pharmacogenomics data can guide the prescription and/or dosing of anti-infective drugs, shifting infectious disease management toward personalized care.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100136"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148259148","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":"Are we underestimating the benefits of lipid-lowering therapies?","authors":"Angela Pirillo, Manuela Casula, Elena Olmastroni, Stefano Scotti, Alberto Corsini, Alberico L Catapano","doi":"10.1016/j.pharmr.2026.100140","DOIUrl":"10.1016/j.pharmr.2026.100140","url":null,"abstract":"<p><p>Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) recognized as a causal factor and the primary target for the prevention of atherosclerotic cardiovascular disease (ASCVD). Currently available lipid-lowering agents, including statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors, can significantly reduce the risk of cardiovascular events across a broad range of patient populations. New oral therapies with novel mechanisms of action and potentially lower costs compared with biologics (including oral proprotein convertase subtilisin/kexin type 9 inhibitors and a new cholesteryl ester transfer protein inhibitor) are under investigation to expand the armamentarium of lipid-lowering drugs and increase the number of patients who can be treated if they prove clinically beneficial. To fully understand the potential health benefits of lipid-lowering therapies, it is essential to consider the concept of cumulative LDL-C exposure and its lifelong impact on ASCVD risk. Genetic studies, Mendelian randomization, and clinical trials consistently demonstrate the cardiovascular benefits of early reduction in LDL-C. However, despite this evidence, treatment gaps, inadequate prescribing, and suboptimal treatment adherence are widespread. The cost-benefit ratio and public health impact emphasize the potential of LDL-C lowering to prevent cardiovascular events and reduce the health care burden. In addition to LDL-C, other risk factors such as lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein B must be considered, whereas nonlipid-based mechanisms of atheroprotection, such as inflammation modulation and thrombogenic risk reduction, are also being explored. The future of lipid-lowering and ASCVD prevention requires a more individualized lipid management strategy to optimize cardiovascular outcomes across the lifespan. SIGNIFICANCE STATEMENT: Early and sustained low-density lipoprotein cholesterol reduction dramatically reduces lifelong cardiovascular risk; however, the adoption of lipid-lowering strategies in clinical practice remains suboptimal. Bridging this gap by understanding the true potential of lipid-lowering therapies could significantly reduce the global burden of atherosclerotic disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100140"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148176485","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":"Translational medications development for methamphetamine use disorder: A systematic review of preclinical, human laboratory, and clinical research.","authors":"Alexandra N Johansen, Mark A Smith, William W Stoops","doi":"10.1016/j.pharmr.2026.100145","DOIUrl":"10.1016/j.pharmr.2026.100145","url":null,"abstract":"<p><p>The prevalence of methamphetamine use disorder (MUD) remains discouragingly high. Relatively few clinical trials have focused on identifying new pharmacotherapies for MUD, and no medications have received US Food and Drug Administration approval. The lack of available pharmacotherapies may be due to failure to follow a rational, translational medications development pipeline progressing from preclinical work to the human laboratory to clinical trials. Our review thus has 2 primary goals: to (1) assess the scope of the literature evaluating candidate medications for MUD and (2) identify drugs screened to treat MUD across research domains, analyzing concordance across contexts. We identified 36 randomized, double-blind, placebo-controlled clinical trials that evaluated 25 candidate medications for MUD. Only 5 of these putative treatments (aripiprazole, bupropion, d-amphetamine, modafinil, and naltrexone) had also been evaluated in human laboratory and preclinical laboratory contexts. Overall, most studies showed no change in methamphetamine use (ie, no effects of treatment) across contexts. Although literature from these contexts imply a high degree of negative predictive validity, we encountered limitations at each level of analysis that prevented us from fully confirming concordance (eg, lack of positive predictive validity). These trends and limitations highlight the extent to which methamphetamine treatments are under-researched relative to other substance use disorders, such as cocaine use disorder. To address this gap in the literature, we advocate for future work that identifies therapeutic targets and, by consequence, classes of medications (repurposed or novel) to treat MUD. We conclude this review with additional comments about future research directions and treatment considerations. SIGNIFICANCE STATEMENT: Investment in methamphetamine use disorder (MUD) medications development remains poor. To date, no pharmacotherapies have received US Food and Drug Administration (FDA) approval to treat MUD, and few candidate medications have been systematically evaluated using a translational medications development pipeline (eg, beginning with preclinical research and progressing to human laboratory research and clinical trials). Adhering to the translational pipeline while incorporating new FDA guidance, such as evaluating nonabstinence outcomes, may be useful in facilitating MUD medications development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100145"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278305","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":"International Union of Basic and Clinical Pharmacology. CXXII. Applying an objective evaluation to the status of class A orphan G protein-coupled receptors.","authors":"Stephen P H Alexander, Kirstie A Bennett, Andrew J Brown, Michelle Glass, David E Gloriam, Julien Hanson, Paul A Insel, Eamonn Kelly, Christopher J Langmead, Kirill A Martemyanov, Rick R Neubig, Stefan Offermanns, Mette M Rosenkilde, Gunnar Schulte, Nicola J Smith, Huixian Wu, Elena Faccenda, Simon D Harding, Anthony P Davenport","doi":"10.1016/j.pharmr.2026.100141","DOIUrl":"10.1016/j.pharmr.2026.100141","url":null,"abstract":"<p><p>In this review, we, on behalf of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology, describe criteria for assessing the evidence for pairing receptors with endogenous/physiological ligands for formal receptor deorphanization. This process is illustrated through consideration of the class A G protein-coupled receptors (GPCRs) not yet formally paired with an endogenous/physiological ligand by the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology. Of the 67 orphan class A GPCRs considered, 25 class A GPCRs have no identified endogenous agonists, although 5 (GPR21, GPR27, GPR52, GPR85, and GPR88) have synthetic ligands that have the potential to be used as tools for uncovering physiological roles and further pharmacological properties of these receptors. Surprisingly, 6 orphan GPCRs (GPR135, GPR152, GPR153, MRGPRF, MRGPRG, and MRGPRX3) have no clear pharmacology or phenotype reported following genetic disruption. Thirty-two orphan GPCRs have been paired with at least 1 endogenous agonist (mainly lipids and their derivatives, peptides, and other metabolites), but further characterization is required from the scientific community to validate these results. We identify 10 orphan class A GPCRs for which there are plausible grounds for considering deorphanization: GPR4 (protons), GPR15 (GPR15L), GPR31 (12S-hydroxyeicosatetraenoic acid), GPR39 (zinc divalent ions, Zn²⁺), GPR65 (protons), GPR68 (protons), GPR132 (9-hydroxyoctadecadienoic acid), GPR183 (7α,25-dihydroxycholesterol), MRGPRD (β-alanine), and MRGPRX1 (bovine adrenal medulla peptide 8-22). The issue of nomenclature for these 10 GPCRs will be considered by further subcommittees of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology. We hope this review will prompt further investigations into these members of the currently most widely clinically exploited protein superfamily. SIGNIFICANCE STATEMENT: The use of systematic, rational nomenclature for drug targets provides a framework to ensure consistent identification and rapid recognition. Given that G protein-coupled receptors have fundamental physiological roles and are widespread targets of drugs in current clinical use, we hope the target summary and deorphanization criteria provided here will prompt renewed efforts to investigate these orphan receptors as regulators of physiology and as opportunities for future therapeutic exploitation.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100141"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219389","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}