Lentiviral-Mediated Expression of a Novel Transforming Growth Factor-β (TGF-β) Inhibitor Peptibody Therapeutically Mitigates Established Liver Fibrosis by Modulating Inflammation and Inducing Metabolic Reprogramming

Chronic liver diseases are characterized by an excessive wound-healing response that leads to liver fibrosis. Effective antifibrotic therapies capable of reversing established fibrosis remain an unmet clinical need. TGF-β signaling is enhanced in fibrosis. Thus, it has become a promising therapeutic target to assist in the recovery of liver function. Previously, we showed that the TβRII-SE/Fc fusion protein exerts a robust prophylactic effect on liver fibrogenesis. In this work we aimed to evaluate the therapeutic effect of TβRII-SE/Fc in a preclinically relevant in vivo model of chronic wound healing. We evaluated the effect of intrahepatic administration of a lentiviral vector encoding TβRII-SE/Fc in a rat CCl4-induced chronic liver injury model. TβRII-SE/Fc lentiviral-mediated liver expression reduces biochemical markers of liver injury. Histological analysis revealed that TβRII-SE/Fc expression significantly diminished CCl4-induced hepatic fibrosis and inflammatory infiltration. In rat livers, TβRII-SE/Fc administration reduced CCl4-induced TGF-β1, TGF-β2, TGF-β3, Col1A1, and proinflammatory cytokine mRNA expressions together with a reduction of α-SMA at protein and mRNA levels. Moreover, by modulating lipid-related genes, TβRII-SE/Fc enhanced hepatic triglyceride levels and restored fatty acid oxidation, consistent with a transient regeneration-associated metabolic phenotype. In the liver, TβRII-SE/Fc modulates inflammation, lipid metabolism, and injury to restore homeostasis after established chronic damage. Additionally, TβRII-SE/Fc induced metabolic reprogramming consistent with a proregenerative hepatic phenotype. TβRII-SE/Fc fusion protein might represent an antifibrotic therapeutic approach targeting established liver fibrosis in chronic liver diseases.