LAUSR

Hepatocellular carcinoma (HCC) is a heterogeneous, late‐diagnosed, and highly recurrent malignancy that often affects the whole body's metabolism. Finding certain theranostic molecules that can address current concerns simultaneously is one of the priorities in HCC management. In this study, performing protein–protein interaction network analysis proposed hepatocyte nuclear factor 4 alpha (HNF4α) as a hub protein, associating epithelial–mesenchymal transition (EMT) to reprogrammed cancer metabolism, formerly known as the Warburg effect. Both phenomena improved the compensation of cancerous cells in competitive conditions. Mounting evidence has demonstrated that HNF4α is commonly downregulated and serves as a tumor suppressor in the HCC. Enhancing the HNF4α mRNA translation through a specific synthetic antisense long non‐coding RNA, profoundly affects both EMT and onco‐metabolic modules in HCC cells. HNF4α overexpression decreased featured mesenchymal transcription factors and improved hepatocytic function, decelerated glycolysis, accelerated gluconeogenesis, and improved dysregulated cholesterol metabolism. Moreover, HNF4α overexpression inhibited the migration, invasion, and proliferation of HCC cells and decreased metastasis rate and tumor growth in xenografted nude mice. Our findings suggest a central regulatory role for HNF4α through its broad access to a wide variety of gene promoters involved in EMT and the Warburg effect in human hepatocytes. This essential impact indicates that HNF4α may be a potential target for HCC treatment.