Our unbiased approach is the first to identify Stat3, Ctnnb1 (β-catenin), and Ep300 as key hub genes specifically in the fructose-driven aggravation of MASLD, suggesting fructose engages a broad pro-inflammatory and pro-fibrotic signaling network not activated by other sugars. This evidence concerns the gene EP300 and metabolic dysfunction-associated steatotic liver disease.