Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent antifibrotics, interferon gamma (IFN gamma), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFN gamma receptor (IFN gamma R) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFN gamma signaling peptide (IFN gamma peptidomimetic, mim gamma) that retains the agonistic activities of IFN gamma but lacks an extracellular receptor recognition sequence for IFN gamma R; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGF beta R)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGF beta R. The synthesized targeted IFN gamma peptidomimetic (mim gamma-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice gamma Treatmentwith mim gamma-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic alpha-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mim. and BiPPB had no effect, and native IFN gamma only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mim gamma-BiPPB, which were substantially observed in mice treated with native IFN gamma. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFN gamma peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases. (C) 2014 Elsevier B.V. All rights reserved.