Pharmacology & Therapeutics最新文献

{"title":"Phytocannabinoids in neurologic, neuropsychiatric, inflammatory, pain, cardiometabolic, hepatic, renal, and neoplastic disorders: Pharmacology, clinical evidence, and translational perspectives.","authors":"Eszter Trojnar, Csaba Matyas, Burhan Yokus, György Haskó, Falk W Lohoff, Raphael Mechoulam, Pal Pacher","doi":"10.1016/j.pharmthera.2026.109135","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.109135","url":null,"abstract":"<p><p>Phytocannabinoids are pharmacologically diverse constituents of Cannabis sativa whose actions go beyond canonical cannabinoid receptors. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are best characterized, while cannabigerol, cannabidivarin, tetrahydrocannabivarin, cannabichromene, cannabinol, and related compounds are emerging candidates. This review integrates molecular pharmacology, pharmacokinetics, safety, and therapeutic evidence across neurologic, neuropsychiatric, inflammatory, pain, cardiovascular and metabolic, hepatic, renal, and neoplastic disorders. The strongest evidence supports pharmaceutical-grade oral CBD as adjunctive therapy for seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, and standardized THC-CBD formulations for selected patients with multiple sclerosis-associated spasticity. Emerging clinical signals in schizophrenia, pain, fibromyalgia, sleep disturbance, substance-use disorders, dermatologic conditions, sickle cell disease, and other symptom-focused indications support continued development. However, efficacy remains compound-, formulation-, exposure-, and indication-specific. In oncology, supportive-care applications must remain distinct from tumor-directed treatment, for which clinical efficacy has not been established. Preclinical studies show coherent effects on neuronal excitability, glial and immune activation, endothelial dysfunction, oxidative and nitrative stress, mitochondrial injury, fibrosis, and regulated cell death. These findings support further investigation in neurodegeneration, ischemia-reperfusion injury, diabetic cardiovascular disease, immune-mediated disorders, hepatic and renal injury, and selected cancers. Translation is constrained by product heterogeneity, variable exposure, uncertain target engagement, model differences, drug interactions, and underpowered trials. Standardized products, exposure-informed dosing, pharmacodynamic biomarkers, responder-enriched designs, and indication-specific randomized studies can address these barriers. Phytocannabinoids therefore represent a promising therapeutic platform whose potential will be best realized by matching defined compounds and formulations to biologically coherent diseases, mechanisms, treatment windows, and patient populations.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"109135"},"PeriodicalIF":13.5,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149356975","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":"Pharmacological targeting of ANO1/TMEM16A in cancer: from channel inhibition to protein downregulation.","authors":"Yohan Seo, Jiyun Lee, Hyorin Song, Yusol Hwang","doi":"10.1016/j.pharmthera.2026.109136","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.109136","url":null,"abstract":"<p><p>Anoctamin 1 (ANO1/TMEM16A) is a calcium-activated chloride channel increasingly recognized as a compelling pharmacological target in oncology. Beyond its role in chloride flux, ANO1 has also been proposed to exert signaling-associated or scaffold-like functions in selected malignancies, including head and neck, breast, and lung cancers. Although pharmacological studies have progressed from broad inhibitors to selective probes and natural products, a critical need has emerged for a rigorous standard to evaluate these agents. A central challenge is distinguishing acute conductance blockade from protein-level downregulation, as these mechanisms may produce distinct biological outcomes. Channel inhibition suppresses ion flux while potentially leaving ANO1-associated protein complexes intact, whereas protein reduction may affect both conductance-dependent and signaling-associated functions; however, the extent to which these functions are mechanistically independent remains incompletely established. Consequently, regulation of ANO1 stability is emerging as a promising therapeutic strategy in tumors with high ANO1 expression and epidermal growth factor receptor (EGFR) activation. However, in clinically relevant EGFR-mutant non-small cell lung cancer models, the role of ANO1 should be interpreted cautiously. Current evidence supports ANO1 as a context-dependent preclinical vulnerability rather than an established mechanism for overcoming osimertinib resistance. To address methodological inconsistencies in the field, this review summarizes ANO1 cancer pharmacology and proposes a conservative operational evidence framework. By establishing strict validation criteria, we classify ANO1 modulators into functional inhibitors, dual modulators, protein-level downregulators, and protein-stability modulators while defining evidence requirements for bona fide targeted degrader designation.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"109136"},"PeriodicalIF":13.5,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316865","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":"Prospects for adiponectin-based therapeutics in myocardial ischemia reperfusion injury.","authors":"M Cecilia Bahit, C Michael Gibson, Yubin Lei, Henry H Hsu, Philipp E Scherer, Gary Sweeney","doi":"10.1016/j.pharmthera.2026.109132","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2026.109132","url":null,"abstract":"<p><p>Adiponectin is an adipocyte-derived hormone with broad cardiometabolic benefits, circulating at high levels in healthy individuals but reduced in obesity, diabetes, and cardiovascular disease. Low adiponectin concentrations are strongly associated with coronary artery disease, myocardial infarction, myocardial ischemia-reperfusion injury (MIRI), and heart failure. MIRI remains a major unmet need in contemporary ST-segment-elevation myocardial infarction (STEMI) care. Although reperfusion is essential in limiting ischemic myocardial necrosis, it causes deleterious effects such as impaired carbohydrate oxidation, excessive fatty-acid oxidation, intracellular acidosis, calcium (Ca²⁺) overload, oxidative/nitrative stress, and mitochondrial fragmentation, that expand infarct size, worsen microvascular obstruction, and fuel adverse ventricular remodeling. Activation of the adiponectin-adiponectin receptor (AdipoR) axis directly counteracts these processes by stimulating adenosine monophosphate-activated protein kinase (AMPK)-dependent metabolic rebalancing, restoring mitochondrial fusion-fission homeostasis, enhancing oxidative capacity, reducing inducible nitric oxide synthase (iNOS-) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated injury, improving endothelial nitric oxide (NO) bioavailability, and enhancing microvascular perfusion. In animal models, adiponectin or its mimetics consistently reduced infarct size, improved myocardial function, and attenuated apoptosis, inflammation, and no-reflow. A growing array of therapeutic strategies has emerged, each bringing its own pharmacologic nuances and implications for translation to the clinic. This review summarizes current strategies to enhance adiponectin action, highlights the progress in peptide and small-molecule mimetics, and discusses future directions for clinical translation in cardiometabolic diseases.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"109132"},"PeriodicalIF":13.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226852","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":"Pharmacological activation of cGAS-STING pathway to reverse cancer drug resistance","authors":"Yumin Wang ,&nbsp;Yan Wang ,&nbsp;Qingzhu Gao ,&nbsp;Yonglin Zhu ,&nbsp;Yulin Li ,&nbsp;Zhe-Sheng Chen ,&nbsp;Junjing Zhang ,&nbsp;Geng Zhang ,&nbsp;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":"2026-04-01","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}

{"title":"Therapeutic potential of targeting novel signaling pathways in regulating chronic inflammation in obstructive lung disorders","authors":"Dan Li ,&nbsp;Ana L. Manzano-Covarrubias ,&nbsp;Kelly B.I. Douglas ,&nbsp;Karim Rafie ,&nbsp;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":"2026-03-01","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}

{"title":"SGLT2 inhibitors: Do they have antiarrhythmic properties?","authors":"Ricardo Caballero,&nbsp;Juan Tamargo,&nbsp;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⁺ 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.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"279 ","pages":"Article 108973"},"PeriodicalIF":12.5,"publicationDate":"2026-03-01","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}

{"title":"A dive into the untapped potential of marine compounds in counteracting neurodegeneration","authors":"Inês Costa ,&nbsp;Daniel José Barbosa ,&nbsp;Fernando Remião ,&nbsp;Maria Emília Sousa ,&nbsp;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":"2026-03-01","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}

{"title":"N6-methyladenosine (m6A) RNA methylation: a potential clinical therapeutic target in cardiocerebrovascular diseases","authors":"Hao Zhang ,&nbsp;Yilin Wu ,&nbsp;Rui Zhao ,&nbsp;Xuhan Hu ,&nbsp;Xiaoou Sun","doi":"10.1016/j.pharmthera.2025.108972","DOIUrl":"10.1016/j.pharmthera.2025.108972","url":null,"abstract":"<div><div>Cardiocerebrovascular disease (CCD) is a condition related to the heart and blood vessels affecting the cardiovascular system. The disease is caused by various pathogenic factors that damage the heart and brain tissues. CCD significantly threatens human health due to the increased incidence, disability, and mortality, but effective treatment options remain lacking. As precision medicine has taken center stage in recent years, the relationship between epigenetics and CCD has been increasingly studied. N6-methyladenosine (m6A) represents a dynamic and reversible methylation occurring on the sixth nitrogen atom of RNA adenine. This modification is essential in epigenetic regulation, involving the coordinated methyltransferase action, methylated reading proteins, and demethylases. Being a prevalent internal modification in eukaryotic messenger ribonucleic acid (mRNA), m6A is indispensable in numerous bioprocesses. m6A modification has been found to govern gene expression at the epigenetic, transcriptional, and post-transcriptional levels. This alteration can affect tumor development, regulate spermatogenesis and hematopoietic stem cell differentiation, thereby serving as a biomarker for CCD diagnosis and prognosis. Accordingly, we reviewed the function, mechanism, and value of m6A modification in CCD to present a fresh perspective for early diagnosis and clinical treatment.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"278 ","pages":"Article 108972"},"PeriodicalIF":12.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822826","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":"Oxidative stress and antioxidant therapeutic mechanisms","authors":"Hengrui Liu ,&nbsp;Yaqi Jiao ,&nbsp;Peng-Chao Wang ,&nbsp;Yingjie Chen ,&nbsp;Maokai Xu ,&nbsp;Xiaojuan Zhang ,&nbsp;Xiaochun Zheng ,&nbsp;Zhenshan Yang","doi":"10.1016/j.pharmthera.2025.108962","DOIUrl":"10.1016/j.pharmthera.2025.108962","url":null,"abstract":"<div><div>Oxidative stress is now understood as a disturbance in the cellular redox balance, involving the accumulation of reactive oxygen, nitrogen, and other reactive species beyond the capacity of antioxidant defenses, with effects that range from essential redox signaling to harmful oxidative damage. Reactive oxygen and nitrogen species are generated from both endogenous metabolic processes and exogenous environmental factors. While controlled levels of oxidative stress contribute to cellular signaling and homeostasis, excessive oxidative damage can lead to pathological conditions, including cardiovascular diseases, diabetes, neurodegenerative disorders, inflammatory conditions, and cancer. To counteract oxidative damage, the body employs a complex antioxidant defense system, comprising endogenous enzymatic and non-enzymatic mechanisms, as well as exogenous dietary antioxidants. Therefore, understanding the regulatory pathways and mechanisms of antioxidants is essential for exploring their role in disease prevention, aging, and immune function. This review provides a comprehensive analysis of oxidative stress, its impact on cellular function, and its involvement in disease pathogenesis. Furthermore, it discusses current therapeutic intervention mechanisms, including dietary strategies, pharmacological antioxidants, and clinical trials evaluating antioxidant efficacy. Finally, emerging research directions, such as novel antioxidant compounds, gene therapy, and personalized antioxidant treatments, are highlighted as potential avenues for future exploration.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"278 ","pages":"Article 108962"},"PeriodicalIF":12.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619571","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":"Sepsis-associated encephalopathy: Unraveling molecular mechanisms, emerging therapeutics, and translational frontiers","authors":"Xinlong Zhang ,&nbsp;Kaizong Huang ,&nbsp;Zixin Wu ,&nbsp;Rui Ding ,&nbsp;Junming Han ,&nbsp;Yuan Zhang ,&nbsp;Yaping Lu ,&nbsp;Yingmei Lu ,&nbsp;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":"2026-02-01","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}