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Microsomal prostaglandin E synthase 1 (mPGES-1) is the terminal regulator of PGE2 synthesis. The expression of mPGES-1 is increased by stimulating inflammatory factors in various human cancers. However, whether hepatitis B virus (HBV) infection affects mPGES-1 and its molecular mechanism in liver cells has not been studied. In this study, we observed that mPGES-1 expression was positively correlated with HBV X protein (HBx) in hepatocellular carcinoma cancerous tissue, and HBx enhanced the mPGES-1 promoter activity in HL7702 liver cells. Mechanistic investigations revealed that HBx can increase the early growth response 1 (EGR1) binding to the transcription site of mPGES-1 promoter. The overexpression and knockdown of EGR1 did not affect cyclooxygenase-2 (COX-2) transcription and expression in HL7702-HBx cells. We also investigated the unique function of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a kind of PGE2 inhibitor, in the regulation of mPGES-1 expression in HBx-positive liver cells. In the presence of 15d-PGJ2, the expression of COX-2 was unaffected, but that of the EGR1-mPGES-1-PGE2 axis was inhibited. Moreover, the capacity of EGR1 binding to the mPGES-1 promoter decreased, and the change in HL7702-HBx cells was more significant. The results indicated that EGR1 is a specific transcription factor in the up-regulation of mPGES-1 expression by HBx, and targeting EGR1 may contribute to inhibiting the change from inflammation to HBV-induced cancer.