Hepatocellular carcinoma (HCC) is a severely lethal cancer that usually originates from chronic liver injury and inflammation. Although progress on diagnosis and treatment is obvious, the cause of HCC remains unclear. In this study, we sought to determine key genes in HCC development. To identify key regulators during HCC progression, we performed transcriptome sequencing to obtain time series gene expression data from a mouse model with diethylnitrosamine-induced liver tumors and further verified gene expression and function and . Among the differentially expressed genes, was continuously downregulated during HCC progression. Overexpression of Cyp2c29 suppressed NF-κB activation and proinflammatory cytokine production by increasing the production of 14,15-epoxyeicosatrienoic acid . Furthermore, overexpression of Cyp2c29 protected against liver inflammation in mouse models of liver injury induced by both acetaminophen and CCl. Two human homologs of mouse , and , were found to be downregulated in human HCC progression, and their expression was positively correlated with overall survival in patients with HCC (significance: = 0.046 and 0.0097, respectively). Collectively, through systematic analysis and verification, we determined that is a novel gene involved in liver injury and inflammation, which may be a potential biomarker for HCC prevention and prognosis determination.