In the current study, we used a range of in vitro and in vivo approaches to address key questions regarding IL11 in hepatocyte biology, NAFLD, and NASH: (1) Defining the role of IL11 signaling in human hepatocytes, (2) examining whether lipotoxicity is related to IL11 activity in hepatocytes, (3) establishing whether IL11 (or IL6) trans-signaling contributes to NASH, (4) dissecting the inter-relationship between IL11 cis-signaling in hepatocytes and the development of steatosis, hepatocyte death, inflammation, and fibrosis. The gene discussed is IL11; the disease is metabolic dysfunction-associated steatotic liver disease.