Dysregulated protein SUMOylation has recently been demonstrated to contribute to human pathobiology, including liver conditions such as hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease (NAFLD).6–8 Prominently, S-adenosylmethionine (SAMe), mainly synthesized in the liver in the first reaction of the methionine cycle by the action of the enzyme methionine adenosyltransferase (MAT) I/III, is a natural inhibitor of UBC9, the sole E2-conjugating enzyme.6 The present study aims to unveil the role of SUMOylation in PLD and evaluate the therapeutic efficacy of SAMe. The gene discussed is UBE2I; the disease is metabolic dysfunction-associated steatotic liver disease.