KANSL3 directs transcriptional programs essential for hepatic metabolism and differentiation [scRNA-seq]

Understanding the molecular mechanisms governing liver homeostasis and disease progression is crucial for developing new therapeutic strategies for chronic liver diseases and liver cancer, with emerging evidence underscoring the key role of epigenetic regulation. Here, we show that hepatic deletion of the epigenetic regulator KANSL3, a component of the NSL complex, causes early-onset chronic liver disease, distinct from metabolic dysfunction-associated steatohepatitis (MASH). Loss of KANSL3 leads to biliary hyperplasia and early hepatic fibrosis, indicating its vital role in liver structure and function. KANSL3 acts as a master regulator of hepatocyte gene expression through histone acetylation, impacting global liver transcriptional networks. scRNA-seq analysis uncovers that KANSL3 deletion disrupts hepatocyte differentiation in vivo and in hepatic organoids. Ultimately, chronic KANSL3 loss alters the liver microenvironment and promotes an immunosuppressive premalignant state linked to hepatocellular carcinoma (HCC).