Rewriting the MASLD‐associated hepatocellular carcinoma script: Targeting epigenetics and metabolism

Abnormal epigenetic patterns are crucial for the progression of metabolic‐associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) development. Recent research focused on the interplay between epigenetics and altered metabolic pathways in HCC from MASLD, suggesting that the reversibility of epigenetic changes offers potential for new therapeutic strategies. However, identifying effective epigenetic targets remains challenging due to the diverse etiologies of HCC. Targeting metabolic reprogramming, MASLD‐associated HCC shows promise in reducing lipid anabolism. In this context, a more comprehensive understanding of metabolomic changes closely tied to druggable epigenetic modifications is of utmost importance. This review provides a concise summary of the key factors driving hepatocarcinogenesis in MASLD and delves deeper into the epigenetic mechanisms. Finally, we aim to present an overview of the primary mechanisms concerning the intricate bidirectional interplay between the metabolome and epigenetic modifications in MASLD‐associated HCC, along with therapeutic strategies specifically targeting epigenetics and metabolomic alterations.