Taken together, the in vitro and in vivo experiments and evaluation of clinical tumors demonstrate that NE-induced sFRP1 and subsequent initiation of Wnt16B/β-catenin signaling play significant roles in the effect of chronic stress on HCC progression, suggesting sFRP1 as a new target for blocking chronic stress-induced tumor progression. Here, SFRP1 is linked to hepatocellular carcinoma.