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Activation of hepatic stellate cells (HSCs) is an essential event in the initiation and progression of liver fibrosis. HSCs are believed to be the major source of collagen-producing myofibroblasts in fibrotic livers. A key feature in the pathogenesis of liver fibrosis is fibrillar Collagen I (Col 1) deposition. Osteopontin (OPN), an extracellular matrix (ECM) cytokine expressed in HSCs, could drive fibrogenesis by modulating the HSC pro-fibrogenic phenotype and Col 1 expression. Here, we aimed to investigate the molecular mechanism of OPN regulating the activation of HSCs. Our results showed that hepatic expression of OPN was increased in patients with liver fibrosis. In addition, hepatic OPN was positively correlated with Col 1 and α-SMA. Recombinant OPN (rOPN) upregulated Col 1 and α-SMA expression in LX-2 cells. However, OPN knockdown downregulated Col 1 expression. The 3′-UTR of the collagen 1 (Col 1) was identified to bind miR-129-5p. Transfection of miR-129-5p mimic in HSC resulted in a marked reduction of Col 1 expression. Conversely, a decrease in miR-129-5p in HSCs transfected by anti-sense miR-129-5p (AS-miR-129-5p) caused Col 1 upregulation. Furthermore, luciferase reporter assay showed that miR-129-5p directly target the 3′-UTR of Col1α1 mRNA via repressing its post-transcriptional activities. Finally, miR-129-5p level was decreased in fibrotic liver of human, and reduced by rOPN treatment. In contrast, miR-129-5p was induced in HSCs transfected by OPN siRNA. These data suggested that OPN induces Col 1 expression via suppression of miR-129-5p in HSCs.