Pharmacological Reviews最新文献

{"title":"Links between COVID-19, long COVID, and neurodegeneration: The role of glycosphingolipids.","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.2026.100113","DOIUrl":"10.1016/j.pharmr.2026.100113","url":null,"abstract":"<p><p>Glycosphingolipids (GSLs) play major roles in viral infections by mediating viral entry and egress from cells in lipid rafts; however, GSLs are also important in neurodegenerative diseases. The role of GSLs in acute COVID-19 infection is critical but remains less-studied in the sequelae of long COVID (post-COVID condition); because the same enzymes that regulate GSL metabolism are critical for viral entry and exit, neuromuscular junctions, neurological function, and cellular metabolism, it is important to determine whether long COVID may increase the risk of subsequent neurodegeneration. SARS-CoV-2 infection alters lipid metabolism and oxygen use and can bind to and modify the expression of neurotrophic GSLs such as GM1 ganglioside. GM1 (N-acetylneuraminic acid) is human-specific and probably evolved as a result of a pandemic 3-2.5 million years ago that drove its selection. GM1 functions as a coreceptor with angiotensin-converting enzyme 2 for SARS-CoV-2 while also being a neurotrophin. Viral multiplication takes place in the endoplasmic reticulum/Golgi apparatus, where GSLs are synthesized. This review defines the complex interaction between viruses, GSLs, and neurodegeneration, which provides new perspectives on the interlinked metabolic changes. A European working group has been set up to assess the risks of neurodegeneration with long COVID, based on potential GSL-mediated mechanisms. SIGNIFICANCE STATEMENT: The SARS-CoV-2 pandemic has resulted in a large number of subjects living with long-term consequences (long COVID). Glycosphingolipids and gangliosides are involved in both viral infections and neurodegeneration; hence, it is important to evaluate whether long COVID may increase the risk of neurodegeneration via this route. This study is the result of a European consortium formed to evaluate this possibility.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100113"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308811","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 evolving landscape of pharmacogenomics: Current achievements and future directions.","authors":"Volker M Lauschke, Magnus Ingelman-Sundberg","doi":"10.1016/j.pharmr.2026.100122","DOIUrl":"10.1016/j.pharmr.2026.100122","url":null,"abstract":"<p><p>Pharmacogenomics investigates how inherited and acquired genetic variation shapes drug efficacy, toxicity, and treatment failure. The major therapeutic areas for pharmacogenomics-assisted drug therapy include oncology, cardiology, psychiatry, neurology, infectious diseases, pain management, and metabolic disorders. Next-generation sequencing has revealed the extensive landscape of pharmacogenetic polymorphisms at the population scale. As a result, the field has evolved from early single-gene pharmacogenetics to genome-wide approaches that encompass the entirety of pharmacogenetic variability. However, much of the heritable variation in drug response remains unexplained, reflecting rare and structural variants, complex haplotypes, and the importance of polymorphisms in factors that regulate pharmacogenes in trans. A recently emphasized factor is the importance of considering differences in substrate specificities between enzymes and transporters that carry amino acid changes. Allele frequencies of actionable genetic variants are often low, requiring large, well powered studies that carefully account for key confounders, including patient adherence, placebo effects, comorbidities, hepatic and renal dysfunction, inflammation, and drug-drug and food-drug interactions. At the same time, emerging in silico variant-effect predictors, deep mutational scanning, population biobanks, and organotypic 3-dimensional human tissue models provide scalable platforms for functionally annotating variants and modeling human drug disposition and toxicity. A major effort moving forward is the continued identification and accurate classification of clinically important drug-gene pairs, along with improved implementation of pharmacogenomics in clinical practice. Artificial intelligence can accelerate this process by enabling rapid genome interpretation, prioritizing clinically relevant variants, and translating complex data into actionable recommendations. It can also integrate pharmacogenomic findings with other omics and help mitigate bias, thereby improving equity in treatment outcomes. In conclusion, the field will continue to expand, but its success will require large, rigorously designed ancestrally diverse trials, harmonized international regulatory standards, robust cost-effectiveness evidence, and the seamless integration of artificial intelligence-supported pharmacogenomic decision tools into global clinical practice. SIGNIFICANCE STATEMENT: Pharmacogenomics is a rapidly evolving field. Here, we review its foundational background, the most important clinical applications, and future perspectives with respect to methodological advances, the role of artificial intelligence, and its translation into clinical practice.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100122"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434681","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":"Erratum to \"Animal models of attention-deficit/hyperactivity disorder: Diversity and validity\" [Pharmacological Reviews 78 (2026) 100108].","authors":"Sarah Bou Sader Nehme, Sandra Sánchez-Sarasúa, Mari-Carmen Medrano, Otmane Bouchatta, Tania Bitar, Abbas Alameddine, Laurent Galineau, Paul Brunault, Nóra Kerekes, Ana-Maria Sanchez-Perez, Walid Hleihel, Marc Landry","doi":"10.1016/j.pharmr.2026.100123","DOIUrl":"10.1016/j.pharmr.2026.100123","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100123"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137664","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 physiopathology to treatment of familial hypercholesterolemia: Existing and emerging pharmacotherapies.","authors":"Arrigo F G Cicero, Maryam Mahjoubin-Tehran, Željko Reiner, Ali H Eid, Tannaz Jamialahmadi, Amirhossein Sahebkar","doi":"10.1016/j.pharmr.2025.100110","DOIUrl":"10.1016/j.pharmr.2025.100110","url":null,"abstract":"<p><p>Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100110"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093743","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 neuroimmune circuits to targeted therapy of chronic pruritus.","authors":"Torben Ramcke, Daniel H Kaplan","doi":"10.1016/j.pharmr.2026.100121","DOIUrl":"10.1016/j.pharmr.2026.100121","url":null,"abstract":"<p><p>Chronic pruritus (CP) is a debilitating symptom of various human diseases and significantly reduces quality of life, underscoring its clinical relevance. CP can accompany non-skin-borne diseases such as chronic kidney disease, but it is also a hallmark of many dermatological diseases. Most pruritic skin diseases are characterized by dysregulated immune responses, indicating a close relationship between CP and skin inflammation. Major breakthroughs over the last 2 decades have transformed our understanding of how immune cells and the nervous system interact to promote itch and scratching behavior in pruritic inflammatory skin diseases such as atopic dermatitis. This bidirectional neuroimmune crosstalk is fundamental for understanding the mechanistic basis of CP and opens new avenues for targeted treatment strategies. This translational review provides an up-to-date overview of the biological basis of itch, its clinical implications, and modern therapeutic options for CP; pruritic inflammatory skin diseases constitute a central focus. The first part summarizes the anatomical structures and physiological processes underlying itch transmission, with emphasis on neuroimmune communication. Endogenous itch-inducing molecules, or pruritogens, are a central element of this crosstalk and drive CP at the neurocutaneous interface. The second part of the review discusses these pruritogens in detail, with particular attention to their clinical relevance for the treatment of CP across dermatological and selected nondermatological conditions. SIGNIFICANCE STATEMENT: Chronic pruritus is a debilitating symptom of many human diseases, including pruritic inflammatory skin diseases such as atopic dermatitis. This review provides an up-to-date overview of the biological basis of itch, highlights neuroimmune crosstalk in particular, and discusses the clinical and therapeutic relevance of pruritogens acting at the neurocutaneous interface.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100121"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459120","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":"Role of solute carrier transporters in the biodistribution and toxicity of chemotherapeutic drugs.","authors":"Mike Boeckman, Thomas Drabison, Arthur Germakovski, Allison Warmuth, Bagdad Ahmed, Anika T Chowdhury, Shuiying Hu, Jason A Sprowl, Alex Sparreboom, Kevin M Huang","doi":"10.1016/j.pharmr.2026.100117","DOIUrl":"10.1016/j.pharmr.2026.100117","url":null,"abstract":"<p><p>Our understanding of the solute carrier (SLC) family of transporters has greatly increased in recent years, especially in oncology, and a wealth of information is now available, indicating that certain SLC family members contribute to the cellular accumulation of small-molecule cancer drugs at sites of injury and to unwanted toxicity in normal tissues. The present review aimed to provide an overview of the toxic effects of commonly used chemotherapy drugs that are associated with SLC-mediated transport, how these associations have been derived, what ensuing intervention strategies have been explored, and how the investigation of these phenomena might change in the near future with the availability of increasingly sophisticated and innovative models and techniques. It is expected that this rapidly emerging field continues to contribute to filling our gaps in knowledge and will aid in the development of interventions aimed at preventing debilitating side effects of cancer drugs and improving the quality of life. SIGNIFICANCE STATEMENT: Toxicities associated with small-molecule chemotherapeutics can be debilitating or even life-threatening and pose a burden on the healthcare system. Improving our understanding of the initiating transporter-mediated mechanisms of these side effects is crucial to the development of preventative or treatment strategies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100117"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776453","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":"Carbon dots for drug delivery: Insights into their potential in nanopharmacology.","authors":"Daniela Iannazzo, Consuelo Celesti, Lucia Cardo, Maurizio Prato, Alessandra Bitto","doi":"10.1016/j.pharmr.2025.100107","DOIUrl":"10.1016/j.pharmr.2025.100107","url":null,"abstract":"<p><p>Carbon dots (CDs), a remarkable class of novel nanomaterials, have attracted significant attention in the biomedical field owing to their extraordinary chemical, physical, and biological properties. Among their diverse applications, CDs stand out as highly promising nanocarriers for drug delivery owing to their ability to cross cell membranes efficiently and deliver therapeutic agents directly to damaged cells or tissues. What makes CDs truly unique is their intrinsic photoluminescence and the abundance of reactive groups on their surface, allowing for extensive multifunctionalization. This versatility enables the conjugation of various functional groups, therapeutic molecules, biomolecules, and targeting ligands, paving the way for an integrated approach to diagnosis and therapy. This review highlights the latest advancements in the application of CDs for drug delivery, focusing on their use in anticancer and antiviral therapies, as well as in the treatment of osteoarticular diseases and neurological disorders. Particular attention is given to the critical aspects of biocompatibility and toxicity, which remain key challenges for their translation into clinical practice. These promising developments position CDs as cutting-edge tools in nanopharmacology, offering exciting opportunities for future therapeutic innovations. SIGNIFICANCE STATEMENT: Carbon dots represent a transformative class of nanomaterials whose tunable chemistry, intrinsic photoluminescence, and high biocompatibility make them highly promising for next-generation drug delivery. By enabling targeted, multifunctional, and trackable therapeutic strategies across cancer, viral infections, osteoarticular, and neurological diseases, carbon dots offer a unique platform that bridges diagnostics and therapy, with the potential to significantly advance precision medicine while addressing current limitations of conventional drug carriers.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100107"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317899","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":"Pharmacology and therapeutics of bile acid synthesis and modification enzymes in metabolic diseases.","authors":"Lili Ding, Lihua Jin, Wendong Huang","doi":"10.1016/j.pharmr.2026.100115","DOIUrl":"10.1016/j.pharmr.2026.100115","url":null,"abstract":"<p><p>Bile acids (BAs) are mainly synthesized in the liver as end products of cholesterol catabolism through the classic (neutral) and alternative (acidic) pathways. BA synthesis requires a coordinated series of enzymes, in which CYP7A1 catalyzes the rate-limiting step, whereas CYP8B1 determines the proportion of the 2 primary BAs-cholic acid and chenodeoxycholic acid. Enterohepatic circulation of BAs is essential not only for nutrient absorption but also for maintaining systemic metabolic homeostasis. The expanding catalog of BA-responsive receptors throughout the gastrointestinal tract and peripheral metabolic tissues underscores the hormone-like nature of BAs in metabolic regulation. Moreover, dynamic and bidirectional interactions between BAs and the gut microbiota introduce an additional layer of complexity that shapes physiological and pathological metabolic processes. Targeting BA synthesis and microbial modification offers substantial therapeutic potential for a wide spectrum of metabolism-related diseases. SIGNIFICANCE STATEMENT: Bile acids (BAs) comprise a large family of endogenous steroid metabolites with diverse chemical structures. They can activate or inhibit a panel of BA-responsive receptors to elicit distinct cellular signaling programs integral to metabolic regulation. Their reciprocal interactions with gut microbiota further amplify the complexity of host metabolic control. Therapeutic strategies that modulate BA synthesis and microbial BA transformation, leveraging both BA synthesis enzymes and microbial partners, hold great promise for treating metabolic disorders.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100115"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195279","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":"Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies.","authors":"Iosif Pediaditakis, Serena Tsakali, Maddie R Lemieux, Matthew Brennan, William H Robinson, Spyridon Papapetropoulos, Andreas Papapetropoulos","doi":"10.1016/j.pharmr.2026.100118","DOIUrl":"10.1016/j.pharmr.2026.100118","url":null,"abstract":"<p><p>The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotection, its restrictive permeability limits therapeutic access, and its dysfunction is increasingly recognized as a driver of pathology across neurodegenerative, inflammatory, cerebrovascular, traumatic, and rare genetic disorders. In this review, we provide a comprehensive overview of pharmacological strategies to modulate BBB function, linking mechanistic insights into tight junction dynamics, transporter networks, endothelial-pericyte interactions, and immune crosstalk to emerging therapeutic approaches. We discuss interventions ranging from small molecules, peptides, and biologics to nanocarriers, noninvasive technologies, gene therapy, and stem cell-based strategies, highlighting their applications in 2 key translational contexts: transient enhancement of drug delivery and restoration of barrier integrity in disease. Ongoing challenges include ensuring safety, accounting for patient heterogeneity, and addressing the limitations of current experimental models. Finally, we consider how advances in BBB-on-chip systems, patient-specific induced pluripotent stem cell-derived models, and novel molecular targets are accelerating translation. Collectively, pharmacological modulation of the BBB, whether by reversible opening to enhance delivery or by reinforcing its protective function, represents a transformative frontier in central nervous system therapy. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a vital safeguard of neural homeostasis and a central obstacle to drug development in the central nervous system. This review integrates mechanistic insights into BBB regulation with translational advances in pharmacology and biotechnology, highlighting strategies that restore barrier integrity in disease and enhance therapeutic delivery. Emerging approaches, including gene therapy, nanotechnology, stem cell-based interventions, and next-generation human-relevant BBB models, illustrate how pharmacological innovation can overcome longstanding challenges and expand therapeutic access to the brain.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100118"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158062","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":"https://doi.org/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":17.3,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}