Pharmacological Reviews最新文献

{"title":"Emerging natural products against obesity and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis: Direct target discovery and mechanistic insights.","authors":"Wei Hu, Meng Gu, Huibo Li, He Li, Juntao Kan, Lingli Zhang, Qian Ding, Yi Zhun Zhu","doi":"10.1016/j.pharmr.2026.100125","DOIUrl":"10.1016/j.pharmr.2026.100125","url":null,"abstract":"<p><p>Obesity is a multifactorial metabolic condition characterized by dysregulated lipid accumulation and systemic energy imbalance with escalating global prevalence. This chronic disease drives a spectrum of life-threatening comorbidities, including metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), which now represent a primary cause of liver-related morbidity and transplantation. Both conditions share pathophysiological underpinnings such as insulin resistance, chronic inflammation, and mitochondrial dysfunction, creating a vicious cycle where obesity exacerbates hepatic steatosis and fibrosis. Although US Food and Drug Administration-approved antiobesity agents such as glucagon-like peptide-1 receptor agonists (eg, semaglutide) demonstrate weight loss efficacy, their long-term utility is constrained by gastrointestinal intolerance and variable effects on hepatic outcomes. Similarly, the recent approval of resmetirom for MASH, though groundbreaking, leaves unresolved challenges in durability, accessibility and some adverse effects including gastrointestinal reaction. The intricate molecular crosstalk linking adipose and hepatocyte dysfunction necessitates innovative therapeutics targeting shared pathophysiological pathways or novel molecular targets. Natural products, with inherent structural diversity and multitarget potential, offer a promising avenue for dual intervention in the obesity-MASH continuum. This review systematically evaluates emerging endogenous metabolites and plant-derived compounds, elucidating their directly validated molecular targets and preclinical evidence for metabolic reprogramming against obesity and MASLD/MASH. Furthermore, it synthesizes translational insights from natural product research and clinical trial experiences of related synthetic agonists. By integrating mechanistic discovery with a critical assessment of developmental challenges, this review aims to advance strategic frameworks for the concurrent management of obesity and MASLD/MASH. SIGNIFICANCE STATEMENT: Obesity-driven metabolic dysfunction-associated steatotic liver disease and steatohepatitis are leading causes of liver morbidity with limited treatment options. This review systematically evaluates natural products as multitarget therapeutics for these interconnected conditions. By integrating evidence of their efficacy and target mechanisms with modern discovery approaches, this study emphasizes pathways for clinical translation and aims to stimulate future research into novel, mechanism-based interventions.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100125"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639396","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":"Pregnane X receptor in disease: From xenobiotic sensor to therapeutic target.","authors":"Yue Gao, Qingqing Yu, Lingzhi Zhang, Zijian He, Xiao Li, Weibin Ou, Xingrui Wu, Shicheng Fan, Huichang Bi","doi":"10.1016/j.pharmr.2026.100133","DOIUrl":"10.1016/j.pharmr.2026.100133","url":null,"abstract":"<p><p>The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor that serves as a classical and central regulator of xenobiotic metabolism and endogenous metabolic homeostasis. Recent studies have revealed that PXR plays critical roles in the pathogenesis and progression of diseases across multiple organ systems, including hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine disorders. Notably, PXR activation can exert protective effects by improving metabolic balance, reducing inflammation, and preventing fibrosis; however, it may promote disease progression in certain settings, highlighting its dual roles. Advances in pharmacological research have led to the identification of numerous PXR agonists and antagonists, including endogenous ligands, natural products, and synthetic compounds, many of which show therapeutic potential. This review summarizes recent progress on the pharmacological roles of PXR in organ-specific diseases and provides an overview of current strategies targeting PXR, offering new insights into its potential as a therapeutic target. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor traditionally recognized as a master regulator of xenobiotic metabolism. Growing evidence demonstrates that PXR plays important roles beyond drug metabolism, regulating the pathogenesis and progression of hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine diseases. This review summarizes current knowledge on PXR's organ-specific functions and pharmacological modulation, highlighting PXR as a promising drug target across multiple disease contexts.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100133"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777986","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":"Regenerative therapeutics for chronic obstructive pulmonary disease.","authors":"Luke van der Koog, Henry R D Showell, Dyan F Nugraha, Mareike Lehmann, Thomas M Conlon, Ali Önder Yildirim, Rocío Fuentes-Mateos, Hoeke Baarsma, John-Poul Ng-Blichfeldt, Barbro N Melgert, Antonella F M Dost, Janette K Burgess, Stacy L S Yam, Irene H Heijink, Sidrah Ahmed, Margherita Paschini, Evalyne M Jansen, Wouter L J Hinrichs, Jill R Johnson, Xinhui Wu, Anika Nagelkerke, Henderik W Frijlink, Carla F Kim, Reinoud Gosens","doi":"10.1016/j.pharmr.2026.100124","DOIUrl":"10.1016/j.pharmr.2026.100124","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases worldwide, characterized by an accelerated loss of lung function. A key problem underlying COPD is increased tissue destruction in combination with defective lung tissue repair. As current therapies do not modify the progression of the disease, new therapies aimed at restoring lung tissue repair in COPD need to be developed. In an attempt to address this major unmet need, there has been a surge in both preclinical and clinical studies, aiming to identify key mechanisms underpinning defective lung repair and the ability to inhibit or even reverse this defect. This includes small molecules such as retinoids, as well as advanced therapy medicinal products such as cell therapies or therapies with cell-derived products such as extracellular vesicles, or secreted proteins. The results of these endeavors have been variable with failures as well as successful proof-of-concepts. In this review, we provide an overview of the current state of the field, including modes of action of the therapeutics that are or have been considered for lung regeneration, including a discussion on the reasons for failure where relevant. In addition, we discuss hurdles in the clinical development of regenerative therapeutics for COPD including clinical outcomes, route of administration and formulation as these are pivotal considerations moving forward. SIGNIFICANCE STATEMENT: Chronic obstructive pulmonary disease is characterized by progressive alveolar destruction and defective epithelial regeneration. Targetable mechanisms, including cellular senescence, altered mesenchymal-epithelial signaling, and chronic inflammation, impair progenitor function and niche integrity. Therapeutic strategies that restore epithelial repair, including small molecules, biologics, and cell-based approaches, represent a promising path toward disease modification and long-term lung function restoration.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100124"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147486962","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":"Disulfidptosis: A novel cell death mechanism with pathological significance and therapeutic potential in diseases.","authors":"Shaoju Qian, Lin Pan, Guanyu Chen, Fangfang Qiu, Yinghua Ma, Ruixue Li, Jawahar L Mehta, Xianwei Wang","doi":"10.1016/j.pharmr.2026.100127","DOIUrl":"10.1016/j.pharmr.2026.100127","url":null,"abstract":"<p><p>Programmed cell death participates in diverse physiological and pathological processes. The identification of disulfidptosis reveals that disulfide stress-induced cytoskeletal disintegration constitutes a targetable biological process mediated through pathways such as SLC7A11-dependent cystine metabolism, offering potential therapeutic avenues for disease intervention. Disulfidptosis involves activation of specific molecular pathways, including SLC7A11-mediated cystine uptake, NADPH depletion, aberrant intracellular disulfide accumulation, filamentous actin collapse, and dysregulation of the antioxidant system, ultimately leading to cell death and contributing to disease progression. Furthermore, comparison between disulfidptosis and other established cell death modalities, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, further underscores its unique biological characteristics and research significance, enabling intervention in disease progression. By targeting these pathways, we systematically integrated pharmacological agonists and inhibitors of key targets, such as SLC7A11-dependent cystine metabolism, to promote or inhibit disulfidptosis, thereby restoring cellular homeostasis disrupted by diseases including cancer, neurodegeneration, ischemia/reperfusion injury, autoimmune diseases, metabolic syndrome, and sepsis. This highlights the potential of disulfidptosis as a therapeutic target. We identified that therapeutic strategies targeting disulfidptosis converge on the core pathogenic axis of \"redox imbalance, disulfide stress, actin cytoskeleton collapse.\" These strategies exhibit disease-dependent bidirectionality-inducing disulfidptosis to selectively eliminate cancer cells in neoplastic diseases while suppressing this process to protect functional cells in non-neoplastic conditions. This review explores the current understanding of the molecular mechanisms and key regulatory nodes of disulfidptosis, deepening our comprehension of the role of disulfidptosis in human health and disease while revealing actionable targets and future research directions. SIGNIFICANCE STATEMENT: The discovery of disulfidptosis enriches understanding of programmed cell death, providing a foundation for targeting SLC7A11-mediated cystine metabolism and other key pathways to treat various diseases and offering new approaches for managing pathological processes previously considered intractable. As molecular mechanistic understanding advances, these emerging therapeutic strategies may open new research avenues, although clinical translation and efficacy require further validation.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100127"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444469","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":"Thrombin generation and the pharmacodynamics of parenteral anticoagulants.","authors":"Joseph R Shaw, Cheryl L Maier, Michaël Hardy, François Mullier, Jonathan Douxfils, Kenichi Tanaka, Bianca Rocca, Hugo Ten Cate, Paul Y Kim, Marc Carrier, Jean M Connors, Jerrold H Levy","doi":"10.1016/j.pharmr.2026.100135","DOIUrl":"10.1016/j.pharmr.2026.100135","url":null,"abstract":"<p><p>Parenteral anticoagulants are mainstay therapies in critical care and perioperative settings because of their unique pharmacological properties, but they have a narrow therapeutic window. This emphasizes the need to thoroughly understand their pharmacodynamics effects on hemostasis. Thrombin generation assays provide a comprehensive measure of coagulation and can characterize class-specific anticoagulant effects. We reviewed the literature with a focus on parenteral anticoagulants to define the role of thrombin generation as a pharmacodynamic measure of anticoagulation status. We contextualize these results in light of findings from a prior review on the effects of oral anticoagulants on thrombin generation and consider our findings in view of results stemming from comparative anticoagulation-focused epidemiologic research. This review provides proof of principle that, from a pharmacodynamics perspective, not all anticoagulants are the same. They exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects, such as unfractionated or low-molecular-weight heparins, are better able to suppress thrombin generation than selective direct inhibitors, such as bivalirudin, argatroban, direct oral anticoagulants, or factor XI(a) inhibitors. We propose a conceptually valid theoretical framework, grounded in mechanistic rationale, supported by experimentation, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants. The knowledge reviewed herein may support the future development of more personalized approaches to anticoagulation treatment. Our findings contribute a foundation upon which future anticoagulation research can be based and warrant further investigation. SIGNIFICANCE STATEMENT: From a pharmacodynamic perspective, not all anticoagulants are the same. Oral and parenteral anticoagulants exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects are better able to suppress thrombin generation than selective direct inhibitors. This review proposes a theoretical framework, grounded in mechanistic rationale, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100135"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856949","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 receptors and inflammation resolution signaling networks in the heart: Pharmacology and potential for innovative therapeutics.","authors":"Deanna K Sosnowski, Terence E Hébert, Dobromir Dobrev, Stanley Nattel","doi":"10.1016/j.pharmr.2026.100129","DOIUrl":"10.1016/j.pharmr.2026.100129","url":null,"abstract":"<p><p>Chronic, unresolved inflammation, and immune system activation contribute to the development and progression of human cardiovascular disease. Specialized proresolving mediators (SPMs), primarily the lipoxins and resolvins, demonstrate potent inflammation-resolving effects. SPMs bind to their respective G protein-coupled receptors (GPCRs) to transduce intracellular events and exert proresolving actions. Given the importance of immune cells in the cardiovascular system, the involvement of nonimmune cardiac cell-types in chronic cardiac inflammation, and the inflammation-resolving effects of SPMs, SPM-GPCR interactions may present efficacious new therapeutic targets for heart disease. In this review, we discuss the mechanisms potentially underlying these GPCR-mediated responses. We begin by providing a brief overview of SPM biosynthesis and the GPCRs implicated in SPM signaling. We then discuss literature demonstrating protective effects of SPMs in models of heart disease. We look in detail at the pharmacology of SPM-GPCR interactions, with a primary focus on formyl peptide receptor 2, GPR32, GPR18, and chemerin receptor 1. We then consider SPM-GPCR downstream signaling pathways in various cell models, including heterologous cell systems overexpressing human SPM-GPCR constructs, SPM-GPCR interactions in endogenous immune cells and effects in nonimmune cell types of the heart including cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. We end by considering knowledge gaps and discussing future directions in SPM-GPCR interaction research. SPM-GPCR signaling networks and actions vary widely in different cell-types and disease contexts, and knowledge of the detailed pharmacology in the heart is quite limited, so extensive additional work on SPM-GPCR signaling is needed to capitalize on the rich therapeutic potential. SIGNIFICANCE STATEMENT: Inflammation resolution is a critical process in cardiac healing after injury or disease. Understanding of the pharmacology and G protein-coupled receptor-dependent signaling mechanisms of inflammation-resolving molecules in the heart is limited, heavily dependent on cell type, and sometimes conflicting. The knowledge gained about these signaling mechanisms in more basic cell systems can be used to facilitate future investigation of how these molecules work within the diverse cardiac cellular milieu as potential targeted therapeutics for heart disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100129"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513782","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. CXXI. Apelin receptor pharmacology in the human cardiovascular system and emerging clinical applications.","authors":"Anthony P Davenport, Thomas L Williams, Duuamene Nyimanu, Robyn G C Macrae, Rhoda E Kuc, Fiona A Chapman, Peiran Yang, Neeraj Dhaun, Janet J Maguire","doi":"10.1016/j.pharmr.2026.100130","DOIUrl":"10.1016/j.pharmr.2026.100130","url":null,"abstract":"<p><p>The apelin receptor binds 2 families of endogenous peptide, apelin and Elabela, but unusually these share little sequence similarity in the N-terminal sequences of the binding domains. Cryo-electron microscopy, X-ray crystallography combined with AlphaFold has yielded a molecular map of the interaction of amino acids with the apelin receptor in complex with endogenous peptides and biased ligands. In the early embryo, the apelin signaling pathway is essential for cardiovascular development, with receptor knockout models displaying severe cardiovascular defects. In adults, the principal short-term effects of [Pyr¹]apelin-13, infused into healthy volunteers was increased cardiac output and decreased peripheral resistance without side effects. Importantly, these beneficial effects of systemic apelin were retained in patients with heart failure and pulmonary arterial hypertension. In chronic kidney disease, [Pyr¹]apelin-13 showed additional therapeutic potential, increasing glomerular filtration rate while reducing proteinuria. Identification of these favorable actions in disease has sparked the development of more effective agonists with improved pharmacokinetics and pharmacodynamics profiles. Among these are G protein-biased peptide agonists, designed to minimize receptor desensitization by reducing internalization via the β-arrestin pathway. These have shown efficacy in proof-of-concept studies and in animal models of pulmonary arterial hypertension, one of the most promising therapeutic targets. This review focuses on the clinical pharmacology of the apelin receptor, exploring the pathophysiology of diseases where the apelin signaling pathway is dysregulated that have emerged during the last 5 years. SIGNIFICANCE STATEMENT: This review focuses on the pharmacology of the apelin receptor where structural analysis has generated a molecular map of interaction with endogenous ligands, apelin and Elabela, as well as with peptide and small molecule agonists. Novel unbiased and biased apelin agonists are progressing through the clinic targeting pathophysiological conditions where the apelin signaling pathway is dysregulated.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100130"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531593","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":"Immunomodulatory and anticancer effects of phytochemicals: A comprehensive analysis.","authors":"Mohamed A Eltokhy, Marina Curcic, Shadan Modaresahmadi, Shreyas Gaikwad, Ninh M La-Beck, Sanjay K Srivastava","doi":"10.1016/j.pharmr.2026.100134","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100134","url":null,"abstract":"<p><p>Natural compounds have been a part of traditional medicine for generations, and recent studies are now recognizing their potential to influence the immune system in cancer treatment. This review focuses on how specific plant-derived chemicals can modulate immune checkpoints such as PD-1, PD-L1, and CTLA-4, which play a central role in cancer immunotherapy, mainly in preclinical and early translational studies. Compounds including curcumin, isothiocyanates, apigenin, luteolin, and berberine demonstrate mechanisms that inhibit immune evasion, are associated with enhanced cytotoxic T-cell responses, and modulate the tumor microenvironment, primarily in the in vitro and in vivo models. Several other phytochemicals such as anthocyanins, triptolide, and epigallocatechin gallate, have shown promise in preclinical models by disrupting oncogenic signaling pathways and promoting antitumor immunity. Although many of these agents face challenges such as low bioavailability, advances in drug delivery systems, and synergistic combinations with current therapies offer a compelling direction for potential cancer treatments. Understanding the molecular interactions of these natural agents can provide hypothesis generation and novel insights into potential effective and less toxic immunotherapeutic approaches. This comprehensive review further provides a thorough understanding of phytochemicals' translational and mechanistic relevance, highlights knowledge gaps, and guides future research directions that could improve integrative cancer immunotherapy techniques, noting that most of the available evidences are derived from preclinical studies. SIGNIFICANCE STATEMENT: Accumulating evidence suggests that phytochemicals modulate immune responses within the tumor microenvironment. These compounds have diverse mechanisms, ranging from cytokine modulation to effects on macrophages, T-cells, and pathways such as STAT3, NF-κB, and PD-L1. This review clarifies how phytochemicals influence immunotherapy outcomes and how they might be used more deliberately in cancer care. Unlike prior reviews, this work explicitly classifies phytochemicals according to whether they enhance antitumor immunity, suppress immune activation, or exert context-dependent dual effects relevant to immune checkpoint therapy.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100134"},"PeriodicalIF":17.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006313","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":"Preclinical abuse potential testing using behavioral economics and drug self-administration demand-curve analysis: A strategy to improve resolution of drug stratification for regulatory control.","authors":"Matthew L Banks, S Stevens Negus, Neil B Varshneya, Chad J Reissig, Dominic Chiapperino, Justin C Strickland, Derek D Reed, Steven R Hursh, David N Kearns","doi":"10.1016/j.pharmr.2025.100112","DOIUrl":"10.1016/j.pharmr.2025.100112","url":null,"abstract":"<p><p>New chemical entities (NCEs) that act on the central nervous system are synthesized in pharmaceutical drug development programs for investigational purposes or by clandestine laboratories for illicit purposes. One component in the regulatory evaluation process of any NCE is abuse potential assessment, which involves both preclinical and human laboratory experiments to compare a NCE with an established and validated positive control that has known abuse potential in humans. Although multiple procedures are available in both preclinical and human laboratories, this review has focused on preclinical drug self-administration procedures because these results are heavily weighted in the regulatory evaluation process. Preclinical drug self-administration procedures have demonstrated high predictive validity for human abuse potential, and procedures that use simple fixed-ratio schedules of reinforcement, as recommended by the current U.S. Food and Drug Administration guidance, have good sensitivity for detecting drug reinforcement and abuse potential. However, these procedures have displayed poor resolution for ranking NCEs along an abuse-potential continuum that may inform controlled substance schedule placement. This review discusses the utility of behavioral economic/demand-curve experimental designs as a method to improve the resolution for differentiating relative reinforcing strength across drugs and ranking abuse potential for considerations of regulatory control. Theoretical benefits of demand-curve analysis are considered, and experimental parameters that optimize those benefits are reviewed. The influence of chronic drug exposure and history on demand-curve metrics of drug reinforcing strength and abuse potential is also reviewed. Future directions are highlighted toward empirically determining the utility of behavioral economic approaches for preclinical abuse potential assessment. SIGNIFICANCE STATEMENT: Simple fixed-ratio schedules of reinforcement have good sensitivity for detecting drug reinforcement and abuse potential but have poor resolution for ranking chemical entities along an abuse-potential continuum. Behavioral economic/demand-curve approaches maybe a method to increase resolution for abuse potential assessment. Accordingly, a preclinical abuse potential algorithm incorporating both simple fixed-ratio schedules and behavioral economic/demand-curve methods is described. Finally, the manuscript describes how individual subject traits and state variables, including chronic drug exposure and history, impact behavioral economic metrics of drug abuse potential.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100112"},"PeriodicalIF":20.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119863","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":"Gut microbiome and bile acid metabolism in liver disease: Mechanisms, clinical implications, and therapeutic opportunities.","authors":"Huiping Zhou, Yi Huang, Chen Chen, Meiyi Song, Phillip B Hylemon","doi":"10.1016/j.pharmr.2026.100120","DOIUrl":"10.1016/j.pharmr.2026.100120","url":null,"abstract":"<p><p>The intricate interplay between the gut microbiome and bile acid metabolism via the gut-liver axis is fundamental to hepatic homeostasis. Perturbations in this axis are increasingly implicated in the pathogenesis of diverse liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. This review integrates current understanding of hepatic bile acid synthesis, enterohepatic circulation, and gut microbial bile acid transformations, detailing how bile acids function as signaling molecules through nuclear receptors including farnesoid X receptor, pregnane X receptor, vitamin D receptor, constitutive androstane receptor, and G-protein-coupled receptors; G protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), and sphingosine-1-phosphate receptor 2. We explore disease-specific alterations in gut microbiota composition and bile acid profiles in metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and liver cancers, focusing on mechanisms linking gut dysbiosis, impaired intestinal barrier function, altered bile acid signaling, inflammation, and immune modulation to liver injury and progression. Furthermore, we discuss the clinical implications, highlighting the potential of microbiome signatures and bile acid profiles as diagnostic and prognostic biomarkers. Therapeutic strategies targeting the gut-liver axis, including probiotics, fecal microbiota transplantation, farnesoid X receptor agonists, and fibroblast growth factor 19 analogs, are reviewed. Finally, we address current challenges and future directions, emphasizing the need for multiomics integration, functional studies, and personalized medicine approaches to leverage the gut-liver axis for improved liver disease management. SIGNIFICANCE STATEMENT: Disruption of the gut microbiome-bile acid-liver axis is now recognized as a unifying mechanism driving multiple liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. Unraveling the molecular and microbial interactions within this axis offers fundamental insights into disease pathogenesis and reveals novel therapeutic opportunities. Integrating multiomics technologies with artificial intelligence-based analytics will accelerate the discovery of predictive biomarkers and personalized interventions, advancing the field toward precision-based liver disease treatment protocols.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100120"},"PeriodicalIF":20.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13258129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317921","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}