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Activated hepatic stellate cells (HSCs) play a crucial role in the development of liver fibrosis. Noninvasive monitoring of the activation of HSCs has been challenging due to the lack of specific receptors or motifs on the cells. The present study provides the evidence that integrin αvβ3 expressed on HSCs is a biomarker reflecting the activation of HSCs. Solid-phase synthesis of cRGDyK (Arg-Gly-Asp-DTyr-Lys) peptide and FAM-conjugated peptide were employed for binding to integrin αvβ3. The increased expression of integrin αv and β3 at mRNA and protein levels was detected during HSC activation. The affinity of cRGDyK to integrin αvβ3 was examined by both radioligand binding assay and FAM-conjugated peptide binding measurements. Quantitative RT-PCR and Western blotting showed a less dramatic, but significant increase in αv and β3 integrin mRNA and protein expression following activation of rat HSCs. Radioiodinated cRGDyK binds to both purified and membrane-bound integrin αvβ3 with high affinity in a dissociable manner. FAM-conjugated cRGDyK was coupled to activated HSCs in a time- and dose-dependent, receptor-mediated manner. Activated HSCs express sufficient number of integrin αvβ3 receptor. cRGDyK peptide binds to both purified and membrane-bound integrin αvβ3 with high affinity in a reversible fashion. Thus, the cRGDyK peptide represented a new agent potentially useful for the diagnosis of liver fibrosis.