Our findings shed some light on the mechanism by which POLB maintains circadian homeostasis, and triggers the HCC progression in a circadian-dependent manner by mediating the demethylation on the 5′UTR of Per1. Because POLB is clinically upregulated in human HCC samples and positively correlated with patient poor prognosis, targeting POLB from a chronobiological perspective could be an attractive strategy for the precise intervention in HCC. This evidence concerns the gene POLB and hepatocellular carcinoma.