Using a series of in vitro and in vivo assays, we provided evidence that nuclear STEAP3 significantly enhances HCC cells proliferation by promoting stemness phenotype and cell cycle progression via upregulating the expression and nuclear trafficking of EGFR and modulating EGFR-RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling axes. Here, STEAP3 is linked to hepatocellular carcinoma.