Maternal palmitic acid overload establishes a SETD1A-dependent epigenetic memory that programs offspring susceptibility to metabolic liver disease

Metabolic dysfunction-associated fatty liver disease (MASLD) has emerged as a major global health concern, with prevalence rising alarmingly in the pediatric population. Maternal nutrition and maternal body mass index (BMI) influence the propensity of the offspring to develop MASLD during childhood and adulthood, but the mechanisms underlying this maternal inheritance are unknown. Here, we have explored the developmental origins of MASLD, focusing on the effect of maternal nutrition and its epigenetic consequences in offspring. Using a mouse model, we demonstrate that maternal consumption of a Palmitic Acid-enriched High-Fat and high-sugar Diet (PA-HFD) during pregnancy and lactation induces stable epigenetic modifications, particularly related to H3K4me3 deposition, in the liver of male offspring through the action of the histone methyltransferase SET1a/COMPASS. This imprinting establishes a persistent transcriptional reprogramming, notably an enrichment in genes governing fatty acid β-oxidation, generating a fasted hepatocyte-like phenotype. Integrated transcriptomic, proteomic and metabolomic analyses reveal that upon re-exposure to a HFD in adulthood, this epigenetically primed hepatic state drives exaggerated metabolic responses, including lipidome reprogramming, leading to exacerbated hepatic steatosis, peroxisomal hyperactivation, oxidative stress, toxic lipid accumulation, and impaired glucose tolerance. Importantly, these gene expression and lipidome changes predict the severity of metabolic liver disease later in life, and can be recapitulated in human pluripotent stem cell-derived hepatocytes when Plamitic Acid is exposed in developmental stage. Moreover, genetic or pharmacological inhibition of SETD1A/COMPASS eliminates the priming marks, restores hepatic transcriptomic programs, and reduces circulating insulin levels and hepatic steatosis in vivo. Together, our findings identify a mechanistic epigenetic link between maternal nutrition and lifelong MASLD susceptibility and uncover a therapeutic strategy to erase the intergenerational transmission of MASLD predisposition.