Trying to decode the intriguing and seemingly complicated role of IL-6 in MASLD, we could hypothesize that IL-6 may act on the hepatocytes in early MASLD through its cis-signaling, thus exerting a possibly anti-steatotic effect; however, when MASLD advances IL-6 may act on other cells, including HSCs, through its trans-signaling, thus contributing to hepatic inflammation and fibrosis. This evidence concerns the gene IL6 and metabolic dysfunction-associated steatotic liver disease.