SOX4 regulates STAT6 to modulate MTHFD2 Expression and Impacts Drug Resistance in Hepatocellular Carcinoma

SOX4 overexpression in hepatocellular carcinoma (HCC) is linked to poor prognosis, modulating gene expression via epigenetic mechanisms. This study reveals SOX4 interacts with DNA demethylases to reduce STAT6 promoter methylation, enhancing STAT6 transcripts. SOX4-STAT6 regulates MTHFD2, critical for NADPH and purine synthesis. Elevated SOX4, STAT6, and MTHFD2 levels correlate with immunotherapy resistance and poor outcomes in HCC. Targeting STAT6 and MTHFD2 in TKI-resistant HCC tumors suppressed growth, highlighting the therapeutic potential of disrupting the SOX4/STAT6/MTHFD2 axis in HCC progression and drug resistance. Overall design: Analyze the DNA methylation sequence of Hep3B and Hep3B SOX4 knockout cells to understand how SOX4 regulates gene expression through DNA methylation.