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Due to its complex pathophysiology, treatment options remain limited. Transforming growth factor \u03b2 (TGF-\u03b2) is a pleiotropic cytokine involved in the regulation of liver fibrosis and metabolism. Previously, we have demonstrated the antifibrotic effect of T\u03b2RII-SE\/Fc delivered by a lentiviral vector (Lv) in a liver fibrosis model. T\u03b2RII-SE\/Fc is a fusion protein composed of the soluble isoform of the TGF-\u03b2 type II receptor (T\u03b2RII-SE) and the human IgG-Fc domain. In this study, we evaluated the potential of T\u03b2RII-SE\/Fc to attenuate key metabolic and hepatic features in an early stage MASLD model using lentiviral-mediated hepatic overexpression. We studied the effect of intrahepatic administration of Lv.T\u03b2RII-SE\/Fc in a rat MASLD model induced by a Western diet. To achieve that, body composition-related parameters, biochemical, histological, ultrastructural, and RT-qPCR analyses were performed. Intrahepatic delivery of Lv.T\u03b2RII-SE\/Fc is associated with improvements in several features of MASLD: (i) Attenuated liver microvesicular steatosis. (ii) Reduced liver fibrosis, together with decreased IL-6 and TGF-\u03b22 gene expression. (iii) Changes in the expression of genes associated with free fatty acid (FFA) utilization, uptake, and de novo lipogenesis in the liver. (iv) Reduced lipid droplet accumulation and mitochondrial swelling, consistent with preserved hepatocellular ultrastructure. (v) Ameliorated insulin resistance (IR) and decreased basal serum glycemia, and (vi) reduced abdominal circumference (AC) and epididymal fat mass. Our findings suggest that T\u03b2RII-SE\/Fc may represent a promising therapeutic candidate for early stage MASLD, with beneficial effects on liver steatosis, fibrosis, and metabolic dysfunction.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00410","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:04:25Z","timestamp":1790589865000},"page":"2960-2972","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic Overexpression\nof a Novel Soluble Endogenous\nTransforming Growth Factor \u03b2 Type II Receptor\u2013Immunoglobulin\nG1 Fc Fusion Protein (T\u03b2RII-SE\/Fc) Attenuates Early Stage Metabolic\nDysfunction-Associated Steatotic Liver Disease in Rats"],"prefix":"10.1021","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3058-0231","authenticated-orcid":true,"given":"Carolina Anahi\u0301","family":"Ca\u0301mara","sequence":"first","affiliation":[{"name":"Universidad Nacional de Mar del Plata , , , ,","place":["Mar del Plata, Buenos Aires, Argentina, B7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela","family":"La Colla","sequence":"additional","affiliation":[{"name":"Universidad Nacional de Mar del Plata , , , ,","place":["Mar del Plata, Buenos Aires, Argentina, B7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania Melina","family":"Rodri\u0301guez","sequence":"additional","affiliation":[{"name":"Instituto Tecnolo\u0301gico de Chascomu\u0301s (INTECH), CONICET-UNSAM , , ,","place":["Chascomu\u0301s, Argentina, B7130"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-2745","authenticated-orcid":true,"given":"Ricardo Alfredo","family":"Dewey","sequence":"additional","affiliation":[{"name":"Instituto Tecnolo\u0301gico de Chascomu\u0301s (INTECH), CONICET-UNSAM , , ,","place":["Chascomu\u0301s, Argentina, B7130"]},{"name":"Universidad Nacional de San Marti\u0301n (UNSAM) , , ,","place":["Buenos Aires, Argentina, B1650"]},{"name":"Hospital de Alta Complejidad en Red \u201cEl Cruce\u201d Nestor Carlos Kirchner , , ,","place":["Florencio Varela, Argentina, B1888"]},{"name":"RADBIO S.A.S , ,","place":["Sunchales, Argentina, S2322"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9351-0138","authenticated-orcid":true,"given":"Andrea","family":"Chisari","sequence":"additional","affiliation":[{"name":"Universidad Nacional de Mar del Plata , , , ,","place":["Mar del Plata, Buenos Aires, Argentina, B7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"2026100909103539700_cit1","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","article-title":"Epidemiology of metabolic dysfunction-associated\nsteatotic liver disease","volume":"31","author":"Younossi","year":"2025","journal-title":"Clin Mol. 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Mol. Med."},{"issue":"7","key":"2026100909103539700_cit5","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1111\/liv.15930","article-title":"The first MASH drug therapy on the horizon: Current\nperspectives of resmetirom","volume":"44","author":"Petta","year":"2024","journal-title":"Liver Int."},{"key":"2026100909103539700_cit6","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.ejim.2024.01.005","article-title":"Dietary and\npharmacological treatment in patients with\nmetabolic-dysfunction associated steatotic liver disease","volume":"122","author":"Armandi","year":"2024","journal-title":"Eur. J. Intern. 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