As long been known, males are more susceptible to hepatocellular carcinoma(HCC) than females, but the reason still remains elusive.In this study, we found that long non-coding RNA five prime to Xist (Inc-FTX) transcribed from X chromosome inactivation center is gender related that its expression was higher in female liver than in male, and is down-regulated in human HCC tissues.A series of experiments demonstrated that Inc-FTX plays a negative role in HCC progress by inhibiting HCC cell proliferation, migration and invasion.Lnc-FTX binds to minichromosome maintenance complex component 2 (MCM2) and impedes DNA replication in HCC cells.On the other hand, Inc-FTX represses wnt/β-catenin signaling activity by competitively sponging the miR-374 family and inhibits HCC cell EMT and invasion.In female, high level of Inc-FTX in liver inhibits HCC initiation by repressing MCM2 involved DNA replication.While after HCC initiation in male, low level of Inc-FTX is bounded by elevated MCM2 protein resulting in increased wnt/β-catenin activity, metastasis capacity, and tumor progress than female.Thus, these findings suggest that tumor suppressor Inc-FTX highly expressed in female is one of the important reasons for HCC gender disparity and may contribute to HCC treatment.