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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. We recently discovered that neuronal regeneration-related protein (NREP/P311), an epigenetically regulated gene reprogrammed by parental metabolic syndrome, is downregulated in human NAFLD. To investigate the impact of NREP insufficiency, we used RNA-sequencing, lipidomics, and antibody microarrays on primary human hepatocytes. NREP knockdown induced transcriptomic remodeling that overlapped with key pathways impacted in human steatosis and steatohepatitis. Additionally, we observed enrichment of pathways involving phosphatidylinositol signaling and one-carbon metabolism. Lipidomics analyses also revealed an increase in cholesterol esters and triglycerides and decreased phosphatidylcholine levels in NREP-deficient hepatocytes. Signalomics identified calcium signaling as a potential mediator of NREP insufficiency's effects. Our results, together with the encouraging observation that several single nucleotide polymorphisms (SNPs) spanning the NREP locus are associated with metabolic traits, provide a strong rationale for targeting hepatic NREP to improve NAFLD pathophysiology. [Display omitted] • NREP deficiency mimics key pathways of human NAFLD • Lack of NREP leads to increased cholesterol and decreased phosphatidylcholine • Calcium signaling is a potential mediator of NREP deficiency • Targeting hepatic NREP provides a promising strategy for improving NAFLD "De Jesus et al. demonstrate that NREP deficiency in human hepatocytes leads to transcriptomic remodeling and metabolic dysregulation, resembling key pathways implicated in NAFLD. One carbon metabolism emerges as a potential mediator, highlighting NREP as a promising therapeutic target for improving NAFLD pathophysiology. These findings provide valuable insights into the molecular mechanisms underlying NAFLD progression.". [ABSTRACT FROM AUTHOR]