{"title":"Introduction to the Theme \"New Approaches, Technology, and Techniques That Advance Pharmacology and Toxicology\".","authors":"Paul A Insel, Amrita Ahluwalia, Susan G Amara","doi":"10.1146/annurev-pharmtox-082525-041413","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-082525-041413","url":null,"abstract":"<p><p>Volume 66 of the <i>Annual Review of Pharmacology and Toxicology</i> includes numerous articles that reveal evolving ideas and insights in pharmacology and toxicology. The major theme is new approaches, technology and techniques. New ideas include the use of systems biology, multiomics, and artificial intelligence to support wellness, prevention, early detection of disease, and precision medicine. Other reviews highlight new ideas and approaches to treat infectious diseases, including the repurposing of drugs approved for other indications and long-acting therapeutics. Related reviews emphasize aspects of global health. One review discusses psychedelics as therapeutics. Several reviews discuss advances in drug discovery modalities. Others relate to a variety of topics in toxicology, including aspects of mitochondrial biology, e-cigarettes, air pollution, microplastics, and nanoplastics. These reviews and others in this volume inform readers about recent advances in pharmacology and toxicology and show how both specialties continue to be vital for improving health and safety globally.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190596","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":"A Mechanistic Framework for Repurposing FDA-Approved Drugs to Combat Antimicrobial Resistance: The Case of <i>Staphylococcus aureus</i>.","authors":"Daniel Sun, Victor Nizet","doi":"10.1146/annurev-pharmtox-062624-014243","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062624-014243","url":null,"abstract":"<p><p>The global rise of antibiotic-resistant bacteria poses a critical threat to healthcare systems, challenging researchers to stay ahead of evolving pathogens. Among the most concerning are invasive infections caused by <i>Staphylococcus aureus</i> (SA), where morbidity and mortality remain high despite advances in care. Resistance in SA has emerged rapidly after the introduction of new antibiotics, limiting treatment options and prompting an urgent need for alternatives. While developing new antimicrobials remains essential, repurposing FDA-approved drugs-originally developed for noninfectious indications-offers a complementary strategy. These agents have known safety and pharmacokinetic profiles and may impact bacterial virulence, antibiotic susceptibility, or host immunity to improve outcomes. This review highlights recent advances in SA drug repurposing, focusing on six mechanistic categories: inhibition of virulence factors, antibiotic resensitization, enhanced susceptibility to innate immunity, host cell protection, augmentation of immune functions, and modulation of pathological inflammation. Together, these strategies offer a multifaceted framework to improve SA infection outcomes using existing therapeutics.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147544","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}
Noa Rappaport, Bartek Nogal, Kevin Perrott, Vincenzo Domina, Leroy Hood, Nathan D Price
{"title":"Early Detection of Wellness-to-Disease Transitions in the AI Era: Implications for Pharmacology and Toxicology.","authors":"Noa Rappaport, Bartek Nogal, Kevin Perrott, Vincenzo Domina, Leroy Hood, Nathan D Price","doi":"10.1146/annurev-pharmtox-062124-013423","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062124-013423","url":null,"abstract":"<p><p>Precision medicine demands a shift from static, single-analyte diagnostics toward dynamic, systems-level understanding of health and disease. This review explores how the convergence of systems biology, multiomics, and artificial intelligence (AI) redefines biomarker discovery to drive early disease detection and personalized intervention. We highlight pioneering efforts that use longitudinal, multimodal data to map individual health trajectories and uncover early disease signals. Advances in AI, including machine learning and contextualization using knowledge graphs and digital twins, are accelerating clinical translation by enabling predictive, context-aware analyses. Real-world applications, including omics-informed diagnostics and digital health monitoring, demonstrate the potential of this approach to transform health care from reactive treatment to proactive wellness. These technologies also inform the development of targeted therapeutics that intervene earlier, personalize treatment, and potentially halt or reverse disease progression. We outline challenges, emerging solutions, and future directions that position AI-driven systems biology at the center of next-generation precision health.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147722","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":"Cross-Organ Mitochondrial Communication in Stress and Disease.","authors":"Koning Shen, Jenni Durieux, Andrew Dillin","doi":"10.1146/annurev-pharmtox-062124-024150","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062124-024150","url":null,"abstract":"<p><p>Growing evidence points to mitochondria as not just the \"powerhouse of the cell\" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123964","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":"Enhancing Large-Scale Pharmacogenetic Studies in African Populations for Clinical Care and Drug Development.","authors":"Abdoulaye Yalcouyé, Kevin Esoh, Ambroise Wonkam","doi":"10.1146/annurev-pharmtox-071724-014737","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-071724-014737","url":null,"abstract":"<p><p>African populations remain largely underrepresented in genomic studies despite their high genetic diversity. The significant variability in drug efficacy and toxicity across different ancestry populations should trigger more diversified and inclusive pharmacogenomic (PGx) studies. Non-European populations, especially Africans, remain largely underrepresented in GWASs and other genomic studies despite their high genetic diversity, which holds information critical for better understanding drug-related toxicity and enhancing the development of new drugs. Therefore, studies using population genetic clustering, polygenic risk scores, high-throughput organoid models, and multiomics analysis are urgently needed in African populations to enhance pharmacogenomics and drug development globally. For instance, studies of loss-of-function mutations in <i>PCSK9</i>, commonly found in populations of African descent, have led to the development of PCSK9 inhibitors, which are used globally to reduce hypercholesterolemia and cardiovascular disease risk. More studies on diverse African populations could elevate PGx, drug development, and therapeutics as illustrated by the PCSK9 example.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123988","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":"From Cell Reprogramming to Tissue Rejuvenation: Countering Aging by Targeting a Gerozyme.","authors":"Helen M Blau, Ermelinda Porpiglia","doi":"10.1146/annurev-pharmtox-071724-100856","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-071724-100856","url":null,"abstract":"<p><p>Here I highlight personal and professional experiences that shaped my career and defined my scientific journey, with my longtime colleague, Ermelinda Porpiglia. I hope that sharing my life's adventures will inspire others to enjoy both a fulfilling scientific career and the fruits of parenthood. I have always enjoyed addressing big questions and challenging dogma. In my early career I probed cell plasticity, challenging the dogma that a cell's specialized state is fixed and irreversible. I then sought to understand stem cells, crucial to tissue repair. Most recently, my lab discovered a gerozyme, 15-prostaglandin dehydrogenase (15-PGDH), a master regulator of muscle aging, and showed that muscle tissue is rejuvenated and strengthened when the gerozyme is inhibited with a small-molecule drug. It would be a dream come true if this discovery in my lab becomes a treatment for the debilitating muscle wasting arising from disuse, disease, or aging.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090918","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}
Olivia Hoffman, Nicholas H Varvel, Avtar S Roopra, Ray Dingledine
{"title":"Neuroinflammation and Disease: Pathways and Opportunities.","authors":"Olivia Hoffman, Nicholas H Varvel, Avtar S Roopra, Ray Dingledine","doi":"10.1146/annurev-pharmtox-062124-043519","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062124-043519","url":null,"abstract":"<p><p>We explore three emerging molecular pathways driving neuroinflammation in chronic and acute brain diseases: the EP2 receptor for prostaglandin E2, the CCR2 receptor for chemokine CCL2, and JAK/STAT signaling. Inflammation is now recognized as a causative factor in neurodegenerative disorders, with neuroinflammation preceding symptom onset in Alzheimer's disease and likely heralding the onset of epilepsy and Parkinson's disease. The EP2 receptor modulates immune cell activation and exacerbates inflammatory responses, while CCR2 regulates peripheral immune cell recruitment to sites of brain inflammation. JAK/STAT pathways regulate neuronal and glial function across brain regions and can both amplify and resolve neuroinflammatory processes. These three signaling pathways converge at multiple nodes-immune cell recruitment, cytokine amplification, and transcriptional regulation-establishing feedforward loops that sustain pathology in chronic diseases. Understanding these mechanisms and their complex interactions provides opportunities for novel therapeutic interventions in neurological conditions characterized by inflammation, potentially leading to disease-modifying treatments.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085021","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}
Adeniyi Olagunju, Simone Perazzolo, Zachary R Stephen, Mark Ryan, Xiaolin Xu, Prajith Venkatasubramanian, Shakir Atoyebi, Rachele Delle Fratte, Andrew Owen, Charles Flexner, Rodney J Y Ho
{"title":"The Promises and Prospects of Long-Acting Therapeutics for Treatment and Prevention of Infectious Diseases.","authors":"Adeniyi Olagunju, Simone Perazzolo, Zachary R Stephen, Mark Ryan, Xiaolin Xu, Prajith Venkatasubramanian, Shakir Atoyebi, Rachele Delle Fratte, Andrew Owen, Charles Flexner, Rodney J Y Ho","doi":"10.1146/annurev-pharmtox-071724-100739","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-071724-100739","url":null,"abstract":"<p><p>Long-acting (LA) therapeutics have emerged as a key component of infectious disease treatment and prevention strategies, their uptake fueled by the need to bridge notable gaps with short-acting drug formulations. In this review, we present the key drivers and summarize the enabling technologies. Focusing on infections with significant global disease burden (HIV, hepatitis B and C, tuberculosis, malaria, and COVID-19), the current state of knowledge on approved LA therapeutics and promising innovations currently in development are summarized. The potential role of LA therapeutics as countermeasures for diseases of pandemic potential and new approaches using computational modeling to accelerate their development for pediatric and perinatal health are discussed. Due to complexities in manufacturing, and the diversity of patent-protected technologies, barriers exist for global access to LA products and in upscaling intricate LA formulations. A multipronged strategic framework, including acceleration of equitable access through generic product manufacture, is proposed to realize the full potential of LA therapeutics for global health.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074446","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":"Metabolic and Inflammatory Mechanisms Driving Atrial Fibrillation.","authors":"Lisa Stoll, Elizabeth E Ha, James C Lo","doi":"10.1146/annurev-pharmtox-062124-025403","DOIUrl":"10.1146/annurev-pharmtox-062124-025403","url":null,"abstract":"<p><p>Atrial fibrillation (AF) is a common arrhythmia with a tremendous impact on quality of life and mortality. Its prevalence continues to rise alongside the increasing obesity and type 2 diabetes epidemics, raising a need for improved therapeutic strategies and a better understanding of the factors and mechanisms that drive metabolic disease-associated AF. To this end, the link between AF and metabolic disease is being increasingly explored in observational, clinical, and experimental studies. Chronic inflammation is a hallmark of metabolic disease, and multiple studies have also demonstrated a strong relationship between AF and inflammation. In this review, we discuss recent advances in our understanding of the mechanisms governing the development of AF in the context of metabolism and inflammation, related concepts in therapeutic development, and a novel role for calcitonin in AF.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074465","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}
Shane C Wright, Peter Lindquist, Mette M Rosenkilde, Volker M Lauschke
{"title":"Incretin Signaling Neighborhoods and Adverse Drug Reactions.","authors":"Shane C Wright, Peter Lindquist, Mette M Rosenkilde, Volker M Lauschke","doi":"10.1146/annurev-pharmtox-062124-015046","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062124-015046","url":null,"abstract":"<p><p>In light of the success of blockbuster drugs for type 2 diabetes and obesity based on the GLP-1 hormone, drugmakers have concentrated their efforts on developing new and improved variations that address the route of administration, dosing, pathway selectivity, or polypharmacology. While some of these modifications have demonstrated improved efficacy in clinical studies and offered exciting opportunities for treating other diseases, drug-induced shifts to the conformational landscape of target receptors may have consequences for side effects. Our review summarizes advances in the understanding of the biochemistry, pharmacogenomics, and molecular pharmacology of incretins and their cognate receptors. We further highlight the current landscape of incretin mimetics and discuss how differences in compartmentalized pathway selectivity affect drug action and outcomes.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032577","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}