Nonalcoholic steatohepatitis (NASH) has emerged as a leading cause of chronic liver disease. The incomplete understanding of NASH fibrosis limits pharmacotherapy development. Here we report a molecular link between hepatocytes and hepatic stellate cells (HSCs) in regulating the progression of liver fibrosis via CREBZF-osteopontin (OPN) axis. Hepatocyte-specific CREBZF knockout (CREBZF LKO) mice and their wild-type littermates were divided into groups that were placed on AMLN, MCD or chow diet. Mouse primary hepatocytes were treated with 250 μM PA and 10 ng/ml TNFα, the conditioned medium was collected and then transferred to HSC-T6 cells for 24 hours. Adeno-associated virus-mediated overexpression of OPN or CREBZF was performed in mice via tail vail injection. Human studies have shown that deregulation of CREBZF is associated with pathogenesis of hepatic steatosis and dyslipidemia. Here, we show that CREBZF is markedly elevated in livers of NASH mice, whereas hepatocyte-specific CREBZF knockout mice are prevented from AMLN or MCD diet-induced hepatic inflammation, liver injury and fibrosis. In vivo and in vitro mechanistic studies revealed that a key mechanism linking hepatocyte CREBZF to NASH fibrosis is miR-6964-3p-mediated inhibition of OPN, an extracellular matrix protein that activates fibrogenic genes in hepatic stellate cells. Moreover, the reduction of NASH phenotypes in CREBZF LKO mice was reversed by adeno-associated virus-mediated overexpression of OPN. Thus, CREBZF-OPN axis represents a previously unrecognized intrahepatic crosstalk in the liver that triggers fibrosis progression and contributes to the severity of NASH.