FSCN1-Mediated Hepatic Gluconeogenesis Is Indispensable for Neonatal Mice Survival

Actin-Bundling Protein Fascin1 (FSCN1) is encoded by the Fscn1 gene, and crucial for cytoskeletal remodeling and cellular migration. While previous study linked Fscn1 deficiency to neonatal lethality in mice, the underlying metabolic mechanism remains unexplored. Here, in this study, we report that systemic knockout (KO) of Fscn1 leads to 52.2% mortality within 24 hours post-birth, accompanied by severe hypoglycemia in KO pups compared to other littermates. Remarkably, this lethality was fully rescued by oral glucose administration, indicating a glucose supply-dependent survival mechanism. Surviving Fscn1 KO neonates displayed persistent developmental deficits, including growth retardation and depleted lipid stores, despite intact canonical insulin-regulated hepatic gluconeogenic pathways. Transcriptomic profiling of P0 livers revealed that Fscn1 loss predominantly disrupts metabolic pathway, within the glycerol phosphate shuttle being the most significantly downregulated module. Mechanistically, Fscn1 KO livers exhibited markedly reduced protein levels of glycerol-3-phosphate dehydrogenase isoforms (GPD1/GPD2), key enzymes bridging glycolysis and gluconeogenesis. Consistently, glycerol tolerance tests (GTT) demonstrated impaired glycerol-to-glucose conversion in Fscn1 KO mice, confirming defective glycerol-driven gluconeogenesis. Our findings establish FSCN1 as a novel cytoskeletal-metabolic integrator essential for neonatal survival by sustaining hepatic glucose production from glycerol, thus revealing an unexpected role of actin dynamics in coordinating metabolic adaptation during early postnatal development. Graphical Abstract Highlights FSCN1 deficiency triggers hypoglycemia-driven neonatal mortality by disrupting hepatic glucose production. Fscn1 loss impairs the gluconeogenesis via suppressing GPD1/GPD2 expression, while sparing insulin-regulated gluconeogenesis. Cytoskeletal dysfunction impairs glycerol-to-glucose conversion, revealing actin-metabolism crosstalk in postnatal adaptation.