Our major findings are (1) maternal WD feeding during pregnancy and lactation induces a dysmetabolic phenotype and increased susceptibility to severe MASLD in the male offspring starting from weaning age, which is further exacerbated by multigenerational exposure; (2) the transmission of MASLD risk could partially be explained by isolated maternal hepatic IR; (3) maternal WD feeding is associated with exacerbated mitochondrial dysfunction in the offspring; (4) FGF21 agonism improves MASLD and mitochondrial dysfunction in offspring with a history of maternal WD. Here, FGF21 is linked to Wilson disease.