ACS Pharmacology and Translational Science最新文献

{"title":"Biography as Biology in Drug Development: Bio-Biographical Response States for Translational Pharmacology","authors":"James B. Baker,&nbsp;Arnab Ghatak,&nbsp;Mark R. Cullen,&nbsp;Ralph I. Horwitz","doi":"10.1021/acsptsci.6c00432","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00432","url":null,"abstract":"<p>Molecular stratification has improveddrug development,yet treatmenteffects remain heterogeneous within apparently similar patients. Wepropose that selected lived exposures be studied as bio-biographicalresponse states: prospectively measured combinations of experience,candidate mediator biology, and treatment context that may modifyefficacy, toxicity, adherence, or end point ascertainment. This Perspectivetranslates the concept into a falsifiable development framework. Itdefines pathway-specific hypotheses, consolidates trial-feasible measures,uses immuno-oncology as an implementation test case, and specifiesstage-appropriate evidentiary gates. The framework does not treatadversity as destiny or assume that association establishes causation.It requires reliable measurement, formal interaction estimates, competing-explanationanalyses, independent replication, and a defined decision consequence.Used with these guardrails, biography can complement molecular pharmacologyby revealing reproducible host states that otherwise appear as unexplainedresponse heterogeneity.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2660–2665"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purinergic P2X7 Receptor Antagonism Impairs Aerobic Capacity without Detectable Effect on Cardiac Adaptation to Exercise in Mice","authors":"Naiara de Souza Santos,&nbsp;Izabel Feltrin Fabro,&nbsp;Ana Paula Pinto de Araújo,&nbsp;Beatriz Carminati dos Santos,&nbsp;Tatyana Nery,&nbsp;Sávio de Almeida Ramos,&nbsp;Izabely Guedes da Rosa,&nbsp;Francielly Andressa Felipetti,&nbsp;Amanda Leite Bastos-Pereira,&nbsp;Aderbal S. Aguiar, Jr.","doi":"10.1021/acsptsci.6c00422","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00422","url":null,"abstract":"<p>Adenosine triphosphate (ATP) signaling through the P2X7receptoris an emerging determinant of mitochondrial energy metabolism andphysical fitness, and the receptor is increasingly targeted pharmacologicallyfor its role in inflammation. Whether systemic P2X7 antagonism affectsaerobic capacity and the structural adaptation of the heart to exerciseis unknown. Adult male Swiss mice were studied in a 2 × 2 factorialdesign crossing physical conditioning (sedentary or exercised) withtreatment (saline or the P2X7 antagonist Brilliant Blue G, BBG; 50mg/kg). Exercised animals trained on a treadmill on alternate daysover approximately 4 weeks; maximal oxygen uptake (V̇O₂max) and power were measured by incremental treadmill ergospirometry,and myocardial cardiomyocyte volume density (Vv) was quantified bydesign-based stereology. Aerobic training increased V̇O₂max and cardiomyocyte Vv. BBG reduced V̇O₂max and peak power independently of training and produced a deficitthat widened progressively with workload across the incremental test,indicating a demand-dependent limitation of oxidative performance.Critically, BBG did not detectably alter the exercise-induced increasein cardiomyocyte Vv and showed no interaction with training; motorcoordination, locomotor and exploratory behavior, blood lactate, andbody mass were also unaffected. P2X7 antagonism thus impairs aerobiccapacity without detectable blunting of the structural response ofthe heart to exercise. This functional–structural dissociationpoints to a metabolic process, plausibly mitochondrial, rather thanto cardiac remodeling, although the present sample size bounds ratherthan excludes an effect on cardiac adaptation, and indicates thatP2X7-directed therapies may reduce exercise capacity without producingovert cardiac structural change.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2950–2959"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MCC950-Derived NLRP3 Inflammasome Inhibitor Modulates Glial Inflammatory Signatures and Neuroinflammation after Traumatic Brain Injury","authors":"Céline Decouty-Pérez,&nbsp;María Álvarez-Rubal,&nbsp;Icíar Polo-Fernández,&nbsp;Elena Martínez-Cuevas,&nbsp;Clara Ruiz,&nbsp;Esther Fuertes-Yebra,&nbsp;Mourad Chioua,&nbsp;Daniel Diez-Iriepa,&nbsp;José Marco-Contelles,&nbsp;Inés Valencia,&nbsp;Javier Egea","doi":"10.1021/acsptsci.6c00341","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00341","url":null,"abstract":"<p>The NLRP3 inflammasomeis a central mediator of sterile inflammationand a key therapeutic target to modulate secondary neuroinflammationfollowing traumatic brain injury (TBI). Although the widely used NLRP3inhibitor MCC950 effectively suppresses inflammasome activation inpreclinical models, its clinical development has been limited by safetyconcerns, underscoring the need for next-generation inhibitors withimproved translational potential. Compound <strong>4b</strong>, a structurallyrelated N-sulfonylurea derivative, has been validated as an NLRP3inhibitor in models of peripheral inflammation. However, whether itspharmacological activity translates to the central nervous system(CNS) neuroinflammatory context remains unexplored. Here, we studiedthe pharmacological activity of compound <strong>4b</strong> <em>in vitro</em> and <em>in viv</em>o to assess its potentialapplication in TBI. In primary mouse glial cultures, compound <strong>4b</strong> inhibited NLRP3 inflammasome-mediated interleukin-1β(IL-1β) release in a concentration-dependent manner followingactivation by ATP, nigericin, or monosodium urate crystals. Consistently,compound <strong>4b</strong> reduced ATP-induced inflammasome assembly,as indicated by decreased ASC speck formation. Acute administrationof compound <strong>4b</strong> (10 mg/kg, i.p.) 1 h post-TBI in a mousemodel significantly improved neuromotor recovery and attenuated injury-associatedbody weight loss. These functional improvements were accompanied byreduced expression of proinflammatory and gliosis-related genes, aswell as protein levels of IL-1β in brain tissue, indicatingeffective modulation of neuroinflammatory signaling. These findingsdemonstrate that compound <strong>4b</strong> exerts NLRP3 inhibitoryactivity in CNS-resident innate immune cells and modulates neuroinflammationand functional recovery after TBI, supporting its further developmentas a mechanistically validated NLRP3 inhibitor with translationalrelevance.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2866–2876"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated In Silico and Experimental Insights into Immunomodulatory Toll-Like Receptor 7/8 Agonists with Anticancer Potential","authors":"Pankaj Kumar,&nbsp;Zahid Bashir Zargar,&nbsp;Suraj Pratap Singh,&nbsp;Kushvinder Kumar,&nbsp;Binita Sihag,&nbsp;Shubham Debaje,&nbsp;Abhay T. Sangamwar,&nbsp;Pavitra Ranawat,&nbsp;Gurpal Singh,&nbsp;Ravi Pratap Barnwal,&nbsp;Deepak B. Salunke,&nbsp;Sandip V. Pawar","doi":"10.1021/acsptsci.6c00263","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00263","url":null,"abstract":"<p>Toll-like receptors (TLRs) are keypattern recognition receptorsthat play a central role in regulating and bridging both innate andadaptive immune responses. Notably, TLR7 and TLR8 agonists have gainedsignificant attention as promising therapeutic candidates becauseof their ability to activate immune responses and modulate immunesignaling pathways for treating viral infections, autoimmune disorders,and cancer. Despite the growing interest in the area of immunotherapy,there remains a substantial gap in the development of new immunomodulatorswith improved efficacy and safety profiles. The primary objectiveof the study was to identify and evaluate newly synthesized TLR7/8agonists using integrated <em>in silico</em> and <em>in vivo</em> strategies. Computational analyses, including moleculardocking, molecular dynamics (MD) simulations, pharmacokinetic-pharmacodynamicprofiling, and network pharmacology analysis, revealed favorable bindinginteractions, stability, drug-like properties, and potential targetingof immune- and cancer-related pathways, specifically those relevantto colorectal cancer. <em>In vitro</em> cytotoxicity assaysshowed that the TLR7/8 agonists exhibit dose-dependent effects inboth colorectal cancer cells and RAW 264.7 macrophages. Additionally,the compounds exhibit minimal hemolytic activity, indicating a lowpotential for systemic toxicity. Furthermore, the cell migration assaydemonstrated that several compounds effectively inhibited cancer cellmigration, particularly when combined with 5-fluorouracil (5-FU),suggesting potential anticancer and antimetastatic activity. Overall,these findings integrate molecular-level, system-level, and experimentalvalidation approaches to comprehensively evaluate TLR7/8 agonistsas potential immunotherapeutic agents. However, further comprehensive <em>in vitro</em> and <em>in vivo</em> investigation studiesare necessary to establish the potential of TLR7/8 agonists for usein cancer immunotherapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2821–2841"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Oxidative Stress for Precision Therapy: Reactive Oxygen Species-Responsive Hydrogel-Nanocarrier Systems as Translational Redox Drug-Delivery Platforms","authors":"Rana Haris Abdullah,&nbsp;Rabia Bibi,&nbsp;Faiza Imtiaz","doi":"10.1021/acsptsci.6c00495","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00495","url":null,"abstract":"<p>Reactive oxygen species (ROS) areregulated chemicalsignals thatbecome pathological when production exceeds antioxidant buffering.This duality creates a translational drug-delivery opportunity: therapeuticsystems can be engineered to remain stable under basal redox conditionswhile activating in oxidatively stressed tissues. This Review criticallyevaluates ROS-responsive hydrogel–nanocarrier systems as multiscaleplatforms for localized redox therapy. The discussion is organizedaround quantitative and clinically relevant design logic rather thanbroad cataloging. We first define hydrogels, nanocarriers, redox therapy,and hybrid hydrogel–nanocarrier systems for pharmacology, drug-delivery,and materials-science readers. We then compare physiological and pathologicalROS ranges, common ROS measurement methods, and the in vitro conditionstypically used to test hydrogel responsiveness. Responsive chemistries,including thioketals, aryl boronates, thioethers, disulfides, selenium/telluriummotifs, catechol/polydopamine systems, and nanozyme components, areconnected to material outcomes such as degradation, swelling, self-healing,cargo release, catalytic ROS conversion, and tissue adhesion. Primaryliterature examples are used to link polymer composition, nanocarriertype, payload, route of administration, ROS assay, and therapeuticend point across chronic wounds, infection, cancer, myocardial injury,neural injury, and osteoarthritis. The Review concludes with translationalconsiderations for manufacturability, sterilization, storage stability,biosafety, regulatory classification, and clinically realistic validation.Overall, progress in ROS-responsive therapeutics will depend on matchingdisease-specific redox biology with chemically validated, quantitativelybenchmarked, and pharmacologically meaningful material design.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2734–2745"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Systems Pharmacology Model Predicts Enhanced Antitumor Efficacy of Combined Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) Blockade in a Syngeneic Mouse Model of Breast Cancer","authors":"Yu Zhang,&nbsp;Hanwen Wang,&nbsp;Natsuki Furukawa,&nbsp;Akash Patil,&nbsp;Theinmozhi Arulraj,&nbsp;Aleksander S. Popel","doi":"10.1021/acsptsci.6c00347","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00347","url":null,"abstract":"<p>Immune-checkpoint inhibitors targeting PD-1 and CTLA-4have transformedcancer therapy, yet most patients still fail to respond, and the reasonsremain incompletely understood. To dissect this heterogeneity andsupport translational development, we built a preclinical quantitativesystems pharmacology model of α-PD-1, α-CTLA-4, and theircombination in syngeneic mouse models, calibrating it jointly againstvehicle, monotherapy, and combination tumor growth data. The calibratedmodel captures all four treatment arms across the measured time courseand supports a mechanistic explanation for the observed tumor-growthinhibition based on two distinct mechanisms: α-PD-1 lifts thePD-1/PD-L1 brake on tumor-infiltrating effector T cells, while α-CTLA-4depletes regulatory T cells, in the tumor and in the periphery, throughFc-dependent antibody-dependent cellular cytotoxicity, a mode of actionspecific to the syngeneic mouse setting and distinct from the clinicalmechanism of ipilimumab. Because the two pathways engage differentcell populations, the combination produces antitumor activity beyondwhat either drug achieves alone, with synergy analysis indicatingapproximately 4-fold reciprocal potency synergy. A virtual cohortof 500 mice reproduces this effect, expands the fraction of strongresponders under combination therapy, and identifies the balance betweenIL-2-driven CD4⁺ and CD8⁺ T-cell expansion,together with intrinsic tumor growth rate, as the dominant determinantsof interindividual response. Because the model shares its structuralarchitecture with our previously published human QSP-IO platform,it provides a quantitative scaffold for guiding preclinical-to-clinicalevaluation of checkpoint-combination strategies.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2877–2888"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divergent Hypoxia-Inducible Factor 2-Alpha Signaling in Alcoholic Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease","authors":"Ayantika Santra,&nbsp;Subhasish Maity,&nbsp;Gouthami Kuruvalli,&nbsp;Selvam Arjunan,&nbsp;Saraladevi Selvam,&nbsp;Challaraj Emmanuel ES,&nbsp;Vaddi Damodara Reddy","doi":"10.1021/acsptsci.6c00246","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00246","url":null,"abstract":"<p>Fatty liver disease, including both metabolic dysfunction-associatedsteatotic liver disease (MASLD) and alcoholic liver disease (ALD)types, is an increasing global health issue, with escalating ratesof illness and death. A key player in the progression of these liverdiseases is the hypoxia-inducible factor 2-alpha (HIF-2α), atranscription factor that oversees lipid metabolism, oxidative stress,and inflammation in liver cells. This review aims to summarize theintricate interactions between HIF-2α and various transcriptionalregulators, including peroxisome proliferator-activated receptor alpha(PPARα), sterol regulatory element-binding protein-1c (SREBP1c),neuraminidase 3 (NEU3), and X-box-binding protein 1(XBP1), in hypoxicenvironments often linked to fatty liver disease. The role of HIF-2αin the pathogenesis and progression of alcoholic liver disease remainscomplex and incompletely understood, with evidence suggesting context-dependentand sometimes contradictory effects. However, our study emphasizesHIF-2α’s dual function in facilitating hepatic steatosisand fibrosis by hindering β-oxidation, causing mitochondrialdysfunction, and altering inflammatory pathways. Furthermore, thisreview focuses on summarizing how ethanol metabolism influences theexpression of HIF-2α and examines its subsequent effects onthe balance of bile acids and bilirubin, offering mechanistic insightsinto the pathophysiology of alcoholic liver disease (ALD) in comparisonto MASLD. The review indicates that specifically inhibiting HIF-2αcould hold therapeutic promise for treating both MASLD and ALD, justifyingthe need for additional experimental and clinical research.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2666–2674"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotection Is a Delivery Problem: A First-Medical-Contact Framework for Acute Myocardial Infarction","authors":"Vibhudutta Awasthi,&nbsp;Tarun W. Dasari,&nbsp;Kenichi A. Tanaka","doi":"10.1021/acsptsci.6c00552","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00552","url":null,"abstract":"<p>Dozens of agents that limit reperfusion injury preclinicallyhavefailed clinically. These failures are architectural, not biological:the right biology reaches the wrong place, as the wrong molecule,at the wrong time, judged by the wrong end point. We recast each asa design constraint and specify a staged regimen anchored at firstmedical contact.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"3000–3004"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factor XI(a) Inhibition in Secondary Stroke Prevention: On the Cusp of a New Anticoagulation Paradigm","authors":"Rami A. Al-Horani","doi":"10.1021/acsptsci.6c00298","DOIUrl":"10.1021/acsptsci.6c00298","url":null,"abstract":"<p>Ischemic stroke remains a leading contributor to globalmortalityand long-term disability, while bleeding complications, particularlyintracranial hemorrhage, continue to constrain the use of conventionalantithrombotic therapies for secondary prevention. Factor XI (FXI)has emerged as an attractive therapeutic target because it promotesthrombin amplification and pathological thrombus stabilization whilecontributing only modestly to physiological hemostasis, forming thebasis for “hemostasis-sparing” anticoagulation. CurrentFXI-targeted approaches include oral small-molecule FXIa inhibitors(asundexian and milvexian), antisense oligonucleotides (fesomersen),and monoclonal antibodies (abelacimab and osocimab). Among these,oral FXIa inhibitors appear particularly suited for long-term cerebrovascularprevention because they provide rapid, reversible target inhibition.Phase II trials, including PACIFIC-Stroke and AXIOMATIC-SSP, showedneutral primary efficacy end points but consistently favorable safetyoutcomes. More recently, the phase III OCEANIC-STROKE trial demonstratedthat asundexian 50 mg once daily added to antiplatelet therapy reducedrecurrent ischemic stroke by 26% (HR 0.74; 95% CI 0.65–0.84)without a significant increase in major bleeding among patients withnoncardioembolic stroke. In contrast, OCEANIC-AF showed inferior efficacycompared with apixaban in atrial fibrillation, suggesting that thetherapeutic value of FXIa inhibition is strongly dependent on clinicalcontext. Taken together, this review summarizes the pathophysiologicalrationale, pharmacology, and clinical evidence supporting FXI inhibitionfor secondary ischemic stroke prevention and discusses future precision-medicinestrategies for patient selection.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2675–2687"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic Overexpression of a Novel Soluble Endogenous Transforming Growth Factor β Type II Receptor–Immunoglobulin G1 Fc Fusion Protein (TβRII-SE/Fc) Attenuates Early Stage Metabolic Dysfunction-Associated Steatotic Liver Disease in Rats","authors":"Carolina Anahí Cámara,&nbsp;Anabela La Colla,&nbsp;Tania Melina Rodríguez,&nbsp;Ricardo Alfredo Dewey,&nbsp;Andrea Chisari","doi":"10.1021/acsptsci.6c00410","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00410","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease. Due to its complex pathophysiology,treatment options remain limited. Transforming growth factor β(TGF-β) is a pleiotropic cytokine involved in the regulationof liver fibrosis and metabolism. Previously, we have demonstratedthe antifibrotic effect of TβRII-SE/Fc delivered by a lentiviralvector (Lv) in a liver fibrosis model. TβRII-SE/Fc is a fusionprotein composed of the soluble isoform of the TGF-β type IIreceptor (TβRII-SE) and the human IgG-Fc domain. In this study,we evaluated the potential of TβRII-SE/Fc to attenuate key metabolicand hepatic features in an early stage MASLD model using lentiviral-mediatedhepatic overexpression. We studied the effect of intrahepatic administrationof Lv.TβRII-SE/Fc in a rat MASLD model induced by a Westerndiet. To achieve that, body composition-related parameters, biochemical,histological, ultrastructural, and RT-qPCR analyses were performed.Intrahepatic delivery of Lv.TβRII-SE/Fc is associated with improvementsin several features of MASLD: (i) Attenuated liver microvesicularsteatosis. (ii) Reduced liver fibrosis, together with decreased IL-6and TGF-β2 gene expression. (iii) Changes in the expressionof genes associated with free fatty acid (FFA) utilization, uptake,and <em>de novo</em> lipogenesis in the liver. (iv) Reducedlipid droplet accumulation and mitochondrial swelling, consistentwith preserved hepatocellular ultrastructure. (v) Ameliorated insulinresistance (IR) and decreased basal serum glycemia, and (vi) reducedabdominal circumference (AC) and epididymal fat mass. Our findingssuggest that TβRII-SE/Fc may represent a promising therapeuticcandidate for early stage MASLD, with beneficial effects on liversteatosis, fibrosis, and metabolic dysfunction.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2960–2972"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}