Pharmacological Reviews最新文献

{"title":"The Promise of Biased Ligands in Therapeutics","authors":"Dylan S. Eiger,Jeffrey S. Smith,Sudarshan Rajagopal","doi":"10.1016/j.pharmr.2026.100160","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100160","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"158 1","pages":"100160"},"PeriodicalIF":21.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895655","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":"Hunting gremlins: GREM1 as a new therapeutic target for multiple diseases including glaucoma.","authors":"David P Siderovski, Nishanth Myneni, Monica Botross, Pinkal D Patel, Abbot F Clark","doi":"10.1016/j.pharmr.2026.100152","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100152","url":null,"abstract":"<p><p>The transforming growth factor-β (TGF-β) superfamily of signaling molecules is involved in normal development and homeostasis. However, aberrant signaling among members of the TGF-β superfamily plays an important pathogenic role in numerous diseases. Increased expression of the pleiotropic cytokine and growth factor TGF-β leads to aberrant signaling associated with numerous diseases, including fibrosis of multiple tissues, a wide variety of cancers, obesity and diabetes, and glaucoma, among others. Normally, the profibrotic effects of TGF-β are regulated by concurrent signaling through bone morphogenetic proteins (BMPs). Unfortunately, many disease states exhibit increased expression of the BMP antagonist Gremlin-1 (GREM1), which suppresses this protective effect of BMPs. Targeting TGF-β is challenging as a therapeutic target because TGF-β is still needed for basal signaling required for normal tissue/cell functions. GREM1 is a more attractive therapeutic target because its expression in most tissues is limited after development. However, targeting GREM1 has been very challenging and long considered an \"undruggable\" target. Fortunately, several new approaches, including the discovery of GREM1-directed aptamers, proteolysis targeting chimera small molecules, and neutralizing antibodies, as well as the design of protein-protein interaction inhibitors, are being explored to directly target and inhibit GREM1 pathogenic functions and activities, thereby restoring homeostasis. SIGNIFICANCE STATEMENT: Gremlin-1 (GREM1) is a secreted bone morphogenetic protein antagonist re-expressed in numerous diseases fibrosis, glaucoma, and cancer. Once deemed \"undruggable,\" GREM1 has recently become a validated therapeutic target, exemplified by the current clinical development of GREM1-neutralizing antibodies. Additional experimental strategies represent promising, although still preclinical, approaches to suppress GREM1 activity or enhance its degradation, offering new avenues to restore transforming growth factor-β/bone morphogenetic protein signaling balance in disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 5","pages":"100152"},"PeriodicalIF":20.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888327","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":"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":"","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":"","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":"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}

{"title":"Vein graft failure: Pathophysiology, detection, prevention and emerging therapeutic strategies.","authors":"Simon D Brown, Sandra Sanchez-Esteban, Laura Clark, Katarina Miteva, Georgios Krilis, Rachael O Forsythe, Stuart A Nicklin, Samantha Carmichael, Colin Berry, Nawwar Al-Attar, David E Newby, Andrew H Baker","doi":"10.1016/j.pharmr.2026.100139","DOIUrl":"10.1016/j.pharmr.2026.100139","url":null,"abstract":"<p><p>Coronary and peripheral artery bypass graft surgery remain cornerstones of cardiac and vascular surgery, respectively. They utilize the saphenous vein as the preferred conduit, although it suffers from poor midterm and long-term outcomes, with the grafted vein often becoming occluded. Current therapeutic approaches aim to manage complications rather than prevent graft failure directly, and despite progress, failure rates have remained unchanged in decades, meaning there remains an unmet clinical need for novel therapeutic approaches. As access to the grafted tissue is available at the time of surgery, coronary and peripheral artery bypass graft are particularly suited to perioperative therapeutic manipulation and intervention that can be delivered locally and directly to the tissue immediately before grafting. Ongoing research attempts to uncover novel genes driving bypass graft failure that can be targeted for such therapies. In addition to protein-coding genes, multiple examples of noncoding genes driving graft failure are now described, including microRNAs and long noncoding RNAs with cell type-specific roles. The increasing wealth of single cell, single nuclei and spatial transcriptomic data related to cardiovascular pathologies are revealing novel target loci that could facilitate greater specificity for target manipulation in specific pathogenic cell types. In parallel, extensive research continues to develop advanced imaging techniques that can be used to monitor the patency of grafts over time, and guide the effective design of advanced therapies. Here, we discuss the progress in these areas and highlight how harmony among these will accelerate therapeutic progress toward vein graft disease. SIGNIFICANCE STATEMENT: Coronary or peripheral artery bypass surgery using saphenous vein grafts are among the most commonly performed cardiovascular surgeries for advanced vascular occlusions. However, both suffer from poor long-term graft patency. The continued development of next-generation multiomics technologies and advanced therapies are illuminating new therapeutic targets that offer hope toward novel precision medicines for peripheral and coronary artery bypass graft failure.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100139"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148164058","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":"Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential.","authors":"Raitis Bobrovs, Ninni Elise Olafsen, Samaneh Shabani Åhrling, Jason Matthews","doi":"10.1016/j.pharmr.2026.100146","DOIUrl":"10.1016/j.pharmr.2026.100146","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that has emerged as a key modulator of several physiological and pathological processes. Historically, AHR has been studied for its role as a mediator of the toxic responses of environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Because of this, its potential as a therapeutic target was overlooked. AHR is now regarded as a multifunctional regulator of inflammation, immunity, barrier tissue integrity, metabolism, and cancer biology. AHR signaling is modulated by an array of structurally diverse endogenous, microbial, dietary, pharmaceutical, and xenobiotic ligands. AHR exhibits extensive crosstalk with many signaling pathways, which contributes to highly context-specific biological outcomes. Recent advances and enhanced interest in AHR pharmacology have accelerated the development of therapeutically relevant AHR ligands, including the clinically approved AHR agonist, tapinarof, for the treatment of psoriasis and atopic dermatitis, as well as emerging AHR antagonist strategies in cancer immunotherapy. Structural efforts have succeeded in providing valuable insight into ligand-AHR interactions that will further contribute to improved and rational design of AHR ligands. However, significant challenges remain, including AHR ligand promiscuity, complex negative feedback regulation, extensive signaling crosstalk, and long-term safety concerns. Here, we review the molecular mechanisms of AHR activation, its physiological and pathological functions, and the current advances of its therapeutic targeting. SIGNIFICANCE STATEMENT: The aryl hydrocarbon receptor (AHR) has emerged from its origins in toxicology to become a promising clinically relevant target for the treatment of dermatological, gastroenterological, and autoimmune diseases as well as cancer. This review summarizes the current knowledge of AHR pharmacology, including molecular signaling, endogenous and exogenous ligands, physiological and pathological functions, present and emerging therapeutic targeting strategies, as well as challenges that remain for translation into safe clinical therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100146"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369019","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}