FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survival

• FSCN1 deficiency causes neonatal lethality due to severe hypoglycemia, which can be rescued by glucose supplementation. • FSCN1 is essential for glycerol-driven hepatic gluconeogenesis in neonates, independent of canonical insulin-regulated pathways. • FSCN1 loss downregulates the glycerol phosphate shuttle and reduces GPD1/GPD2 protein levels, impairing glycerol-to-glucose conversion. • This study reveals a novel cytoskeletal-metabolic integration, highlighting FSCN1 as a potential therapeutic target for neonatal metabolic disorders.