Here, using a combination of the MCDD-induced NASH paradigm and unbiased genome-wide RNA sequencing (RNA-seq) analyses, our findings demonstrate that MLL4 acts as a critical epigenetic regulator in the progression of NASH by modulating the NF-κB signaling pathway in hepatocytes and macrophages, highlighting the important role of NF-κB in the inflammatory response associated with NASH. Here, NFKB1 is linked to metabolic dysfunction-associated steatohepatitis.