BACKGROUND & AIMS: Metabolic syndrome is a newly identified risk factor for hepatocellular carcinoma (HCC), however the molecular mechanisms still remain unclear. To elucidate this issue, cross-species analysis was performed to compare gene expression patterns of HCC from human patients and melanocortin 4 receptor-knockout (MC4R-KO) mice, developing HCC with obesity, insulin resistance and dyslipidemia. METHODS: Unsupervised hierarchical clustering and principle component analysis of 746 differentially expressed orthologous genes classified HCC of 152 human patients and MC4R-KO mice into two distinct subgroups, one of which included all the mouse HCC was etiologically associated with metabolic risk factors, such as obesity and diabetes. A specific biomarker was identified by the integrative analysis, and validated with in vitro studies and other cohort patients. RESULTS: As commonly overexpressed in human and mouse metabolic disease-associated HCC, FABP4 was remarkably enriched in intratumoral activated hepatic stellate cells (HSCs). Then, we established subclones constitutively expressing FABP4 from a human HSC cell line, in which the expression levels of inflammatory chemokines including IL1A and IL6 was upregulated through NF-B nuclear translocation. An immunohistochemical validation study of other 106 human HCC samples indicated that FABP4-positive HSCs were distributed in tumors of 38 cases, and that the FABP4-high group was composed of patients with non-viral and non-alcoholic HCC (P=0.027) and with multiple metabolic risk factors (P<0.001) compared with the FABP4-low. CONCLUSIONS: FABP4 overexpression in HSCs could contribute to hepatocellular carcinogenesis in patients with metabolic risk factors via modulation of inflammatory pathway, and is a promising novel biomarker as well as a potential therapeutic target for this subtype of HCC.