Despite being one of the leading causes of cancer-related deaths, there is an unmet clinical need for hepatocellular carcinoma (HCC) patients. The lack of effective treatment is, at least in part, due to our lack of understanding of the molecular pathogenesis of this disease. Oncofetal protein SALL4 is re-activated in patients with aggressive HCC along with other solid tumors and hematologic malignancies. This study identifies a previously unrecognized mechanism of SALL4 reactivation which is mediated by pseudogene-induced demethylation. Using a locus-specific demethylating technology, we identified the critical CpG region for SALL4 expression. We showed that SALL4 pseudogene 5 hypomethylates this region through interaction with DNMT1, resulting in SALL4 upregulation. Intriguingly, pseudogene 5 is significantly upregulated in a hepatitis B virus (HBV) model prior to SALL4 induction, and both are increased in HBV-HCC patients. Our results suggest that pseudogene-mediated demethylation represents a unique mechanism of oncogene activation in cancer. ### Competing Interest Statement The authors have declared no competing interest.

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