Pharmacological Reviews最新文献

{"title":"The complement system: Biology, pathology, and therapeutic interventions.","authors":"Xaria X Li, Trent M Woodruff","doi":"10.1016/j.pharmr.2025.100079","DOIUrl":"10.1016/j.pharmr.2025.100079","url":null,"abstract":"<p><p>Targeting the innate immune complement system has long been pursued as a promising strategy for treating a wide spectrum of acute and chronic immune-mediated disorders. Nearly 2 decades since the approval of the first complement inhibitor targeting C5, the field of complement therapeutics has flourished. In just the past 5 years, 8 new complement-targeting drugs have entered the market. Traditionally dominated by monoclonal antibodies, the approved drug arsenal now includes an ever-expanding selection of macrocyclic peptides, low molecular weight compounds, and aptamers. Other novel approaches in clinical development include recombinant proteins, nanobodies, oligonucleotide therapeutics, and gene therapies. Alongside this remarkable diversification of drug modalities, the complement field is advancing toward deciphering and precisely targeting all pathways of the complement network. Although current approved therapies primarily benefit patients with rare diseases, there is a nascent shift towards addressing more prevalent conditions. In line with this unprecedented expansion in the field, we aim to provide a comprehensive overview of the complement system, its activation pathways, key effector mechanisms, and regulation. We discuss the consequences of unchecked complement activation leading to disease pathologies and highlight therapeutic intervention points within the cascade. We review the discovery and molecular pharmacology of clinically approved and late-phase complement therapeutics, bridging to their clinical pharmacokinetics, safety, and regulatory status for clinical indications. We particularly focus on the diversifying modalities of complement-targeting drugs and evaluate the unique opportunities and challenges these new developments present. With this knowledge, we forecast potential short-term and long-term development trends in the field. SIGNIFICANCE STATEMENT: Therapeutic targeting of the complement system has been widely pursued for treating autoimmune and inflammatory disorders, with the field recently seeing an exponential increase in clinical approvals (8 new drugs during 2022-2024). This timely comprehensive review presents an overview of the complement cascade, its effector mechanisms, and the molecular pharmacology and clinical utility of currently approved and late-phase complement-targeting drugs. We thus provide a valuable one-stop guide for existing and upcoming researchers working in the complement field.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100079"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668087","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":"Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.","authors":"Alina Brüge, Evgeni Ponimaskin, Josephine Labus","doi":"10.1016/j.pharmr.2025.100071","DOIUrl":"10.1016/j.pharmr.2025.100071","url":null,"abstract":"<p><p>More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100071"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626813","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":"How dopamine guides our social world.","authors":"Nancy Padilla-Coreano, Freddyson J Martínez-Rivera","doi":"10.1016/j.pharmr.2025.100085","DOIUrl":"10.1016/j.pharmr.2025.100085","url":null,"abstract":"<p><p>Many species, including humans, rely on social interactions to thrive and survive. These life interactions engage many neural systems, including those used for learning, cognition, and innate behaviors that are fundamentally guided by rewarding processes. Dopamine, a neuromodulator critical for signaling natural rewards, orchestrates a variety of social functions in both health and disease states. Recent advances in tools to manipulate brain circuits and molecular biology in behaving animals have opened new paths to understanding dopamine's role in social functions. In this review, we will discuss recent cross-species studies that are beginning to uncover the role of dopamine and its substrates across 4 main social domains: reward, decision making, stress, and dominance. Finally, we consider the potential implications of this current body of literature for dopamine-associated dysfunctions in neuropsychiatric disorders that impact social interactions. SIGNIFICANCE STATEMENT: As the field of social neuroscience progresses, dopamine and its associated mechanisms emerge as central regulatory entities guiding diverse social behaviors and offer vital clues to their mechanistic processes at the molecular, cellular, and network levels. In this review, the dopamine correlates of social domains were framed in a timely and concise manner while highlighting the gaps in knowledge and future research opportunities in the biology of dopamine that are most relevant to our social world.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100085"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144964162","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":"Pathological and therapeutic roles of bile acid metabolism and signaling in hepatocellular carcinoma: Insights from human and mouse studies.","authors":"Xue Wang, Curtis D Klaassen, Xin Chen, Youcai Zhang","doi":"10.1016/j.pharmr.2025.100073","DOIUrl":"10.1016/j.pharmr.2025.100073","url":null,"abstract":"<p><p>Bile acids (BAs), the end products of cholesterol catabolism, play a crucial role in various physiological and pathological processes. Defects in BA synthetic enzymes and transporters cause rare monogenic diseases. Dysregulation of BA homeostasis contributes to the pathogenesis and progression of various liver diseases, including hepatocellular carcinoma (HCC), the most common form of liver cancer. BA profiles are altered in patients with HCC and in mouse models of HCC, and their diagnostic potential is currently under clinical investigation. Growing evidence suggests that BA metabolism and signaling regulate key processes involved in HCC development. Recent advances in understanding the complex interactions between the gut microbiota and BAs have provided new insights into HCC. In this review, we summarize the current literature on BA quantification, detoxification, synthesis, transport, signaling functions, and the interplay between BAs and bacteria in the pathogenesis and progression of HCC, particularly in patients with HCC and mouse models. Furthermore, we discuss potential therapeutic strategies targeting BA metabolism and signaling as promising approaches for HCC treatment. SIGNIFICANCE STATEMENT: Bile acids hold promise as potential biomarkers for the diagnosis and prognosis of hepatocellular carcinoma. Modulating bile acid metabolism and signaling pathways represents a promising novel strategy for hepatocellular carcinoma treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100073"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554132","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":"Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.","authors":"Xiaodong Cheng, Hua Liu, Wenbo Zhang, Wenli Yang, Fang Mei","doi":"10.1016/j.pharmr.2025.100078","DOIUrl":"10.1016/j.pharmr.2025.100078","url":null,"abstract":"<p><p>Vascular remodeling is a complex process involving the coordinated actions of multiple cellular signaling pathways in various cell types, leading to structural and functional changes in blood vessels. These changes can be adaptive, as in wound healing, or maladaptive, as seen in chronic vascular diseases such as atherosclerosis, hypertension, and retinopathy. Exchange proteins directly activated by cAMP (EPACs) are key players in cAMP-mediated cell signaling, distinct from the more traditionally studied protein kinase A pathway. EPAC proteins are guanine nucleotide exchange factors for the small G proteins Rap1 and Rap2. Recent studies have also revealed noncanonical functions of EPAC1 involving the formation of biomolecular condensates. EPAC proteins regulate various cellular processes, including cell adhesion, migration, proliferation, and differentiation. In this review, we discuss the roles of EPACs in vascular remodeling and diseases associated with the process, as well as the potential of EPACs as therapeutic targets for proliferative vascular diseases. SIGNIFICANCE STATEMENT: Vascular remodeling is associated with various human diseases, such as atherosclerosis, stroke, and retinopathy. Understanding the roles of exchange proteins directly activated by cAMP signaling in vascular remodeling provides insights into the mechanisms underlying vascular diseases and facilitates the development of targeted therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100078"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13169004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708417","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":"Advances and challenges in experimental models of posttraumatic epilepsy for therapeutic interventions.","authors":"Doodipala Samba Reddy, Victoria M Golub, Sreevidya Ramakrishnan, Severn B Churn, Lee A Shapiro, Jaclyn Iannucci, Asla Pitkänen, Aristea S Galanopoulou, Rama Maganti, Detlev Boison","doi":"10.1016/j.pharmr.2025.100080","DOIUrl":"10.1016/j.pharmr.2025.100080","url":null,"abstract":"<p><p>Epilepsy affects over 80 million people worldwide, with approximately 40% experiencing refractory seizures. Despite some progress in deciphering the complex process of epileptogenesis, which transforms a healthy brain into one susceptible to epilepsy, there are still no therapies available to prevent this condition. Traumatic brain injury (TBI) is a leading cause of epilepsy in both military and civilian populations, often leading to the complex condition of posttraumatic epilepsy (PTE). Defined as recurrent seizures following TBI, PTE lacks effective treatment options, highlighting the need for improved experimental models and translational interventions. Unveiling disease-modifying therapeutics for epilepsy is a top priority in the field of neurology research. One major obstacle in PTE research is the lack of robust models that accurately reflect the multifaceted and heterogeneous nature of human PTE. Hence, developing disease-modifying treatments requires innovative models that facilitate the identification of novel therapeutic approaches. Establishing clinically relevant animal models is critical for elucidating the pathophysiological mechanisms of epileptogenesis and identifying effective therapies for PTE management. This article describes the opportunities and challenges associated with advances in PTE experimental models, including the call for common data elements to be developed for PTE. Inspired by insights from a 2023 workshop supported by the American Epilepsy Society, this review explores progress in animal models, experimental protocols, biomarkers, and principles of therapeutic interventions for TBI-induced seizures and posttraumatic epileptogenesis. It evaluates the PTE research landscape and critically discusses current strategies, innovations, hurdles and future directions for establishing models that ultimately lead to the development of disease-modifying agents and targeted therapeutic approaches for PTE prevention. SIGNIFICANCE STATEMENT: Posttraumatic epilepsy (PTE) lacks specific therapies due to limited experimental models. Here, we outline the proceedings of the 2023 American Epilepsy Society-supported National Workshop on PTE, covering small and large animal models for PTE research. This article provides insights into recent advancements in experimental paradigms and analyzes the validity and application of these models in identifying interventions to prevent epileptogenesis following traumatic brain injury. We address challenges and obstacles in discovering PTE therapies, offering clinical data context and common themes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100080"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765136","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":"The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets.","authors":"Fabio A Iannotti, Vincenzo Di Marzo","doi":"10.1016/j.pharmr.2025.100070","DOIUrl":"10.1016/j.pharmr.2025.100070","url":null,"abstract":"<p><p>The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s. It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome). This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer. The importance of other \"eCBomes\" in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being. SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100070"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485480","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":"Immunomodulatory effects of calorie restriction and its mimetics: A new potential therapeutic approach for autoimmune diseases.","authors":"Monokesh K Sen, Eileen Liao, Duan Ni, Anjie Ge, Laura Piccio","doi":"10.1016/j.pharmr.2025.100063","DOIUrl":"10.1016/j.pharmr.2025.100063","url":null,"abstract":"<p><p>Calorie restriction (CR) is a well known intervention associated with multifaceted anti-aging and pro-longevity health benefits. It induces complex physiological cellular and molecular adaptations, resulting in the fine-tuning of metabolic and immune responses in both homeostatic and diseased states. It has thus been extensively studied both preclinically and clinically, uncovering its therapeutic potential against inflammatory conditions, particularly autoimmune diseases. CR mimetics (CRMs), that is, molecules that mimic CR's effects, have also been widely investigated to counteract inflammatory states associated with numerous diseases, including autoimmunity. However, a comprehensive overview of how CR and CRMs modulate different aspects of immune responses, thereby potentially modifying autoimmunity, is still lacking. Here, we reviewed the latest progress on the impacts of CR and CRMs on the immune system and the current evidence on their potential translation in the clinical management of people with autoimmune diseases. First, we summarized different types of CR and CRMs and their main mechanisms of action. We next reviewed comprehensively how CR and CRMs modulate immune cells and discussed up-to-date preclinical and clinical advances in using CR and CRMs in the context of some of the most common autoimmune diseases. Finally, challenges faced in CR-related research and its translation into the clinic are discussed. SIGNIFICANCE STATEMENT: Calorie restriction (CR) encompasses various approaches for daily or intermittent reduction in calorie intake while maintaining adequate nutrient intake. It acts through cell-intrinsic and -extrinsic pathways to modulate immune cell functions. CR is emerging as a strategy for autoimmune disease management. CR's effects could be partially mimicked by molecules called CR mimetics, which are proposed to achieve CR's effects without reducing food intake. CR and CR mimetics have been tested as promising potential therapeutics in preclinical and clinical autoimmune disease studies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100063"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192103","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":"5-HT_2A receptors: Pharmacology and functional selectivity.","authors":"Benjamin R Cummins, Gerald B Billac, David E Nichols, Charles D Nichols","doi":"10.1016/j.pharmr.2025.100059","DOIUrl":"10.1016/j.pharmr.2025.100059","url":null,"abstract":"<p><p>Serotonin 5-HT_2A receptors were one of the first serotonin receptors to be pharmacologically characterized. In mammals, they are expressed throughout the body in nearly every cell and tissue type, with the highest density in cortical layer V of the brain. They are involved in several aspects of normal physiological processes and behaviors and have been implicated in the etiology of neuropsychiatric diseases such as schizophrenia. Atypical antipsychotics have targeted blockade of 5-HT_2A receptors as part of their therapeutic mechanism. More recently, 5-HT_2A receptors have come to prominence for their role as the primary target for psychedelic drugs, which activate this receptor subtype to produce their characteristic behavioral effects. 5-HT_2A receptor agonists like psilocybin, dimethyltryptamine, and lysergic acid diethylamide have each demonstrated long-lasting therapeutic efficacy in clinical trials for psychiatric disorders such as major depression and substance use disorders. There is a significant effort in both academia and industry to develop new agonists of 5-HT_2A receptors with therapeutic efficacy. There are 3 primary scaffolds for agonists: tryptamines, ergolines, and phenylalkylamines, each engaging different subsets of amino acid residues in the receptor binding pocket. Differences can lead to differential responses between ligands for functionally selective outcomes. Here, we provide a historical perspective on 5-HT_2A receptors, their key structural features and motifs involved in ligand-receptor interactions, and how these interactions can affect signaling pathways downstream of the receptor. Understanding how ligands interact with the 5-HT_2A receptor will fundamentally inform future drug discovery to optimize therapeutics for a variety of disorders. SIGNIFICANCE STATEMENT: Psychedelic drugs have demonstrated long-lasting therapeutic efficacy for several conditions in multiple clinical trials. Their target, serotonin 5-HT_2A receptors, are GPCRs with complex pharmacology. Having knowledge of how ligands interact with 5-HT_2A receptors in the orthosteric binding pocket at the structural level to induce specific signal transduction pathways will inform on efforts to design and develop functionally selective drugs to potentially treat a variety of diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100059"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151422","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":"Senotherapy for chronic lung disease.","authors":"Peter J Barnes","doi":"10.1016/j.pharmr.2025.100069","DOIUrl":"10.1016/j.pharmr.2025.100069","url":null,"abstract":"<p><p>Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100069"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485479","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}