Research highlights DNA methylation’s critical influence in autoimmune diseases and hepatocellular carcinoma (HCC). Hypomethylation of interferon genes in SLE and PAD2 overexpression due to hypomethylation in MS reveal epigenetic dysregulation contributing to pathogenesis. In HCC, aberrant methylation silences tumor suppressors and activates oncogenes, reshaping cancer epigenomes. These insights illuminate novel molecular targets and reinforce the importance of epigenetics in disease initiation and progression, opening avenues for biomarker development and therapeutic interventions.