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The molecular mechanism revealing the pathogenesis of non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, remains to be investigated. In the study, we found that secreted modular calcium-binding protein 2 (SMOC2), which belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins, functioned as a positive modulator of NAFLD. SMOC2 expression was markedly up-regulated in human liver samples with NAFLD, and in hepatic tissues of mice fed with HFD. SMOC2 knockout in mice significantly attenuated metabolic disorders, insulin resistance, glucose intolerance and lipid deposition in mice challenged with HFD. Moreover, liver fibrosis induced by HFD was clearly ameliorated by SMOC2 deficiency mainly through inhibiting transforming growth factor (TGF)-β1 expression. Additionally, hepatic inflammatory response triggered by HFD was also improved in SMOC2-knockout mice via inactivating nuclear factor-κB (NF-κB). Mechanically, SMOC2 could interact with TGF-β1, and SMOC2 overexpression markedly increased TGF-β1 in mouse primary hepatocytes, which played an essential role in regulating hepatic steatosis. In conclusion, we provided proof that blocking SMOC2 might be a promising strategy for preventing NAFLD through the interaction with TGF-β1.