Pub Date : 2026-02-05DOI: 10.1016/j.pharmthera.2026.108998
Oscar Solis, Fallon Curry, Zachary Frangos, Will Dunne, Ingrid Schoenborn, Alyssa Lauer, Juan Gomez, Emilya Ventriglia, Jordi Bonaventura, Michael Michaelides
{"title":"An emerging role for synaptic Zn2+ in substance use disorders","authors":"Oscar Solis, Fallon Curry, Zachary Frangos, Will Dunne, Ingrid Schoenborn, Alyssa Lauer, Juan Gomez, Emilya Ventriglia, Jordi Bonaventura, Michael Michaelides","doi":"10.1016/j.pharmthera.2026.108998","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.108998","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"236 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134068","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}
Pub Date : 2026-02-04DOI: 10.1016/j.pharmthera.2026.108995
Alessandro Maino, Jason Leo Walsh, Leonardo Portolan, Rafail Kotronias, Pietro Ameri, Rocco Vergallo, Italo Porto, Filippo Crea, Adrian Banning, Paolo Tammaro, Giovanni Luigi De Maria
{"title":"Therapeutic interventions for coronary microvascular obstruction after acute myocardial infarction: Developments and challenges","authors":"Alessandro Maino, Jason Leo Walsh, Leonardo Portolan, Rafail Kotronias, Pietro Ameri, Rocco Vergallo, Italo Porto, Filippo Crea, Adrian Banning, Paolo Tammaro, Giovanni Luigi De Maria","doi":"10.1016/j.pharmthera.2026.108995","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.108995","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"89 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109914","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}
Pub Date : 2026-02-01DOI: 10.1016/j.pharmthera.2026.108991
Yumin Wang , Yan Wang , Qingzhu Gao , Yonglin Zhu , Yulin Li , Zhe-Sheng Chen , Junjing Zhang , Geng Zhang , Hongquan Wang
Therapeutic resistance remains a major challenge in cancer management. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Cancer cells frequently acquire drug resistance by inhibiting cGAS-STING signaling, leading to growing interest in small-molecule agonists that reactivate this pathway to counter resistance. In this review, we summarize recent molecular and cellular findings explaining how cancer cells suppress cGAS-STING through epigenetic regulation, post-translational modifications (PTMs), and altered metabolic pathways. We also evaluate recent studies on cGAS-STING agonists aimed at restoring sensitivity to chemotherapy, immunotherapy, and targeted cancer therapies to inform new strategies to pharmacologically reactivate cGAS-STING signaling pathway to reverse existing therapeutic barriers.
{"title":"Pharmacological activation of cGAS-STING pathway to reverse cancer drug resistance","authors":"Yumin Wang , Yan Wang , Qingzhu Gao , Yonglin Zhu , Yulin Li , Zhe-Sheng Chen , Junjing Zhang , Geng Zhang , Hongquan Wang","doi":"10.1016/j.pharmthera.2026.108991","DOIUrl":"10.1016/j.pharmthera.2026.108991","url":null,"abstract":"<div><div>Therapeutic resistance remains a major challenge in cancer management. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Cancer cells frequently acquire drug resistance by inhibiting cGAS-STING signaling, leading to growing interest in small-molecule agonists that reactivate this pathway to counter resistance. In this review, we summarize recent molecular and cellular findings explaining how cancer cells suppress cGAS-STING through epigenetic regulation, post-translational modifications (PTMs), and altered metabolic pathways. We also evaluate recent studies on cGAS-STING agonists aimed at restoring sensitivity to chemotherapy, immunotherapy, and targeted cancer therapies to inform new strategies to pharmacologically reactivate cGAS-STING signaling pathway to reverse existing therapeutic barriers.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"280 ","pages":"Article 108991"},"PeriodicalIF":12.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102576","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}
Pub Date : 2026-01-31DOI: 10.1016/j.pharmthera.2026.108994
Gaoyong Hu, Haoyu Li, Renjing Su, Lifeng Han, Tao Wang, Haiyang Yu
{"title":"Unravelling the complexity of cancer premetastatic niche - Mechanistic insights and clinical therapies","authors":"Gaoyong Hu, Haoyu Li, Renjing Su, Lifeng Han, Tao Wang, Haiyang Yu","doi":"10.1016/j.pharmthera.2026.108994","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.108994","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"58 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095685","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}
Pub Date : 2026-01-30DOI: 10.1016/j.pharmthera.2026.108997
Xenia Gonda, Peter Dome, Livia Balogh, Mate Baradits, János M. Réthelyi
{"title":"Connecting the dots and finding the way forward: Pharmacological, neuromodulatory, and psychotherapeutic interventions for the complex treatment of adult ADHD","authors":"Xenia Gonda, Peter Dome, Livia Balogh, Mate Baradits, János M. Réthelyi","doi":"10.1016/j.pharmthera.2026.108997","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.108997","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"93 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089555","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}
Pub Date : 2026-01-30DOI: 10.1016/j.pharmthera.2026.108996
Aldo Bonaventura, Marco Giuseppe Del Buono, Michele Golino, Nicola Potere, Alessandra Vecchié, Danilo Malandrino, Benjamin Van Tassell, Taryn Youngstein, Brittany N. Weber, Antonio Abbate
{"title":"Therapeutic management of inflammatory heart diseases","authors":"Aldo Bonaventura, Marco Giuseppe Del Buono, Michele Golino, Nicola Potere, Alessandra Vecchié, Danilo Malandrino, Benjamin Van Tassell, Taryn Youngstein, Brittany N. Weber, Antonio Abbate","doi":"10.1016/j.pharmthera.2026.108996","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.108996","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"81 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089556","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}
Pub Date : 2026-01-19DOI: 10.1016/j.pharmthera.2026.108983
Dan Li , Ana L. Manzano-Covarrubias , Kelly B.I. Douglas , Karim Rafie , Martina Schmidt
Chronic obstructive pulmonary disease (COPD) and asthma are two major obstructive lung disorders characterized by persistent airway inflammation that leads to progressive lung function decline. Although both chronic in nature, the inflammatory profiles that characterize these diseases differ significantly: COPD is predominantly driven by neutrophilic inflammation, whereas allergic asthma, a major subtype of asthma disease, is traditionally associated with eosinophilic and T helper 2 (Th2)-mediated responses. This review explores first the mechanisms underlying chronic inflammation in COPD and asthma, emphasizing thereafter the impact of bacterial and viral infections in exacerbating inflammatory responses and accelerating lung damage. Current therapeutic approaches, including the use of corticosteroids, bronchodilators, and biologics, are evaluated, highlighting their mechanisms of actions and limitations. Finally, the review focuses on novel therapeutic targets that have emerged from recent advances in (airway) inflammation research. The roles of key signaling pathways such as those involving Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), C-X-C motif chemokine receptor 2 (CXCR2), toll-like receptors (TLRs), tumor necrosis factor (TNF) signaling, P2X purinoceptor 4 (P2X4 receptor), and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in sustaining chronic inflammation are discussed. Understanding these pathways offers insights into the potential for development of more targeted and effective treatments. By offering a comprehensive overview of both established and (potential) novel approaches, this review aims to promote the identification and development of therapeutic strategies that could revolutionize the options for effective treatment of chronic inflammation in obstructive lung disorders.
{"title":"Therapeutic potential of targeting novel signaling pathways in regulating chronic inflammation in obstructive lung disorders","authors":"Dan Li , Ana L. Manzano-Covarrubias , Kelly B.I. Douglas , Karim Rafie , Martina Schmidt","doi":"10.1016/j.pharmthera.2026.108983","DOIUrl":"10.1016/j.pharmthera.2026.108983","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) and asthma are two major obstructive lung disorders characterized by persistent airway inflammation that leads to progressive lung function decline. Although both chronic in nature, the inflammatory profiles that characterize these diseases differ significantly: COPD is predominantly driven by neutrophilic inflammation, whereas allergic asthma, a major subtype of asthma disease, is traditionally associated with eosinophilic and T helper 2 (Th2)-mediated responses. This review explores first the mechanisms underlying chronic inflammation in COPD and asthma, emphasizing thereafter the impact of bacterial and viral infections in exacerbating inflammatory responses and accelerating lung damage. Current therapeutic approaches, including the use of corticosteroids, bronchodilators, and biologics, are evaluated, highlighting their mechanisms of actions and limitations. Finally, the review focuses on novel therapeutic targets that have emerged from recent advances in (airway) inflammation research. The roles of key signaling pathways such as those involving Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), C-X-C motif chemokine receptor 2 (CXCR2), toll-like receptors (TLRs), tumor necrosis factor (TNF) signaling, P2X purinoceptor 4 (P2X4 receptor), and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in sustaining chronic inflammation are discussed. Understanding these pathways offers insights into the potential for development of more targeted and effective treatments. By offering a comprehensive overview of both established and (potential) novel approaches, this review aims to promote the identification and development of therapeutic strategies that could revolutionize the options for effective treatment of chronic inflammation in obstructive lung disorders.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"279 ","pages":"Article 108983"},"PeriodicalIF":12.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000573","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}
Pub Date : 2026-01-12DOI: 10.1016/j.pharmthera.2026.108982
Inês Costa , Daniel José Barbosa , Fernando Remião , Maria Emília Sousa , Renata Silva
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms – including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.
{"title":"A dive into the untapped potential of marine compounds in counteracting neurodegeneration","authors":"Inês Costa , Daniel José Barbosa , Fernando Remião , Maria Emília Sousa , Renata Silva","doi":"10.1016/j.pharmthera.2026.108982","DOIUrl":"10.1016/j.pharmthera.2026.108982","url":null,"abstract":"<div><div>Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms – including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"279 ","pages":"Article 108982"},"PeriodicalIF":12.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962077","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}
Pub Date : 2026-01-05DOI: 10.1016/j.pharmthera.2025.108973
Ricardo Caballero, Juan Tamargo, Eva Delpón
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent the cornerstone of therapy in patients with type 2 diabetes (T2D), heart failure (HF), or chronic kidney disease (CKD). These patients present a high risk of cardiac arrhythmias, particularly when these comorbidities coexist. In experimental models, SGLT2i exert antiarrhythmic effects and clinical studies and meta-analyses strongly suggest that they reduce new-onset and recurrences of atrial fibrillation in patients with HF or CKD irrespective of the diabetic status. Although some trials and meta-analyses suggest that SGLT2i could decrease the risk of ventricular arrhythmias and sudden cardiac arrest, the evidence is weak, and their potential remains to be confirmed. Thus, clinical evidence so far should be considered as hypothesis-generating. Although the exact mechanism underlying their antiarrhythmic effects remains uncertain and much research is needed, multiple direct cardiac and extracardiac effects may be involved. They improve cardiac electrical (via changes in ion channels and transporters; maintenance of Na+ and Ca2+ homeostasis), structural (reduce hypertrophy, fibrosis, inflammation, and epicardial fat; improve mitochondrial function and energetic metabolism), and autonomic (reduce sympathetic hyperactivity) remodelling. Indirect extracardiac effects related to an improvement in cardiovascular risk factors and haemodynamics, together with their protective renal and vascular effects, may also play a role. This narrative review summarises the experimental and clinical evidence of their antiarrhythmic effects, potential underlying mechanisms, limitations of present evidence, and gaps of knowledge that should be filled before SGLT2i can be recommended for the prevention and treatment of arrhythmias in patients for whom these drugs are indicated.
{"title":"SGLT2 inhibitors: Do they have antiarrhythmic properties?","authors":"Ricardo Caballero, Juan Tamargo, Eva Delpón","doi":"10.1016/j.pharmthera.2025.108973","DOIUrl":"10.1016/j.pharmthera.2025.108973","url":null,"abstract":"<div><div>Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent the cornerstone of therapy in patients with type 2 diabetes (T2D), heart failure (HF), or chronic kidney disease (CKD). These patients present a high risk of cardiac arrhythmias, particularly when these comorbidities coexist. In experimental models, SGLT2i exert antiarrhythmic effects and clinical studies and meta-analyses strongly suggest that they reduce new-onset and recurrences of atrial fibrillation in patients with HF or CKD irrespective of the diabetic status. Although some trials and meta-analyses suggest that SGLT2i could decrease the risk of ventricular arrhythmias and sudden cardiac arrest, the evidence is weak, and their potential remains to be confirmed. Thus, clinical evidence so far should be considered as hypothesis-generating. Although the exact mechanism underlying their antiarrhythmic effects remains uncertain and much research is needed, multiple direct cardiac and extracardiac effects may be involved. They improve cardiac electrical (via changes in ion channels and transporters; maintenance of Na<sup>+</sup> and Ca<sup>2+</sup> homeostasis), structural (reduce hypertrophy, fibrosis, inflammation, and epicardial fat; improve mitochondrial function and energetic metabolism), and autonomic (reduce sympathetic hyperactivity) remodelling. Indirect extracardiac effects related to an improvement in cardiovascular risk factors and haemodynamics, together with their protective renal and vascular effects, may also play a role. This narrative review summarises the experimental and clinical evidence of their antiarrhythmic effects, potential underlying mechanisms, limitations of present evidence, and gaps of knowledge that should be filled before SGLT2i can be recommended for the prevention and treatment of arrhythmias in patients for whom these drugs are indicated.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"279 ","pages":"Article 108973"},"PeriodicalIF":12.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902500","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}
Pub Date : 2025-12-26DOI: 10.1016/j.pharmthera.2025.108971
Xinlong Zhang , Kaizong Huang , Zixin Wu , Rui Ding , Junming Han , Yuan Zhang , Yaping Lu , Yingmei Lu , Yanna Si
Sepsis-associated encephalopathy is a debilitating complication of systemic infection, marked by acute cognitive impairment and long-term neurological deficits in the absence of direct central nervous system (CNS) infection. Its pathogenesis involves a multifactorial interplay of neuroinflammation (e.g., cytokine storms), immune dysregulation, blood-brain barrier (BBB) disruption, metabolic derangements, and impaired neuronal repair. These mechanisms synergistically contribute to neuronal injury and persistent cognitive dysfunction. Emerging therapeutic strategies-such as targeted immunomodulators, BBB-stabilizing agents, and novel CNS-targeted drug delivery-aim to interrupt this cascade and improve outcomes. Concurrently, precision medicine approaches leverage molecular profiling to tailor interventions. However, current clinical management remains supportive, hindered by incomplete mechanistic understanding and a paucity of disease-modifying therapies. This review synthesizes recent advances in the pathophysiology of sepsis-associated encephalopathy, critically evaluates these mechanism-based therapeutic approaches, and highlights translational roadblocks in biomarker development and preclinical-to-clinical bridging. We also propose future directions to accelerate the development of targeted pharmacotherapies and personalized treatment paradigms for sepsis-associated encephalopathy.
{"title":"Sepsis-associated encephalopathy: Unraveling molecular mechanisms, emerging therapeutics, and translational frontiers","authors":"Xinlong Zhang , Kaizong Huang , Zixin Wu , Rui Ding , Junming Han , Yuan Zhang , Yaping Lu , Yingmei Lu , Yanna Si","doi":"10.1016/j.pharmthera.2025.108971","DOIUrl":"10.1016/j.pharmthera.2025.108971","url":null,"abstract":"<div><div>Sepsis-associated encephalopathy is a debilitating complication of systemic infection, marked by acute cognitive impairment and long-term neurological deficits in the absence of direct central nervous system (CNS) infection. Its pathogenesis involves a multifactorial interplay of neuroinflammation (e.g., cytokine storms), immune dysregulation, blood-brain barrier (BBB) disruption, metabolic derangements, and impaired neuronal repair. These mechanisms synergistically contribute to neuronal injury and persistent cognitive dysfunction. Emerging therapeutic strategies-such as targeted immunomodulators, BBB-stabilizing agents, and novel CNS-targeted drug delivery-aim to interrupt this cascade and improve outcomes. Concurrently, precision medicine approaches leverage molecular profiling to tailor interventions. However, current clinical management remains supportive, hindered by incomplete mechanistic understanding and a paucity of disease-modifying therapies. This review synthesizes recent advances in the pathophysiology of sepsis-associated encephalopathy, critically evaluates these mechanism-based therapeutic approaches, and highlights translational roadblocks in biomarker development and preclinical-to-clinical bridging. We also propose future directions to accelerate the development of targeted pharmacotherapies and personalized treatment paradigms for sepsis-associated encephalopathy.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"278 ","pages":"Article 108971"},"PeriodicalIF":12.5,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844789","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}
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