HMGCS2 and metabolic dysfunction-associated steatotic liver disease: We show that (1) impaired ketogenesis in HFD-induced NAFLD mice is mediated by reduced hepatic expression of Hmgcs2; (2) Hmgcs2-associated ketogenic deficiency and a fat-enriched dietary composition are both required for postnatal fatty liver development; (3) insufficient level of ketogenic function or Hmgcs2 gene dosage promote adult-onset NAFLD upon HFD; and (4) HMGCS2 OE-mediated ketogenesis activation improves HFD-induced NAFLD and metabolic dysfunction.