YTHDC1 Is Essential for Postnatal Liver Development and Homeostasis

Abstract Hepatocytes play a crucial role in liver function, with their maturation occurring during postnatal development. However, the molecular mechanisms underlying this maturation are not yet fully understood. In this study, YTHDC1 is identified as a key positive regulator of hepatocyte maturation and an essential factor in maintaining liver homeostasis. YTHDC1 expression increases in the liver after birth, and hepatocyte‐specific deletion of Ythdc1 impairs hepatocyte maturation, leading to reduced liver weight, liver injury, inflammation, and fibrosis. These defects contribute to the development of nonalcoholic steatohepatitis and hepatocellular carcinoma in mice. YTHDC1 supports postnatal hepatocyte maturation and liver function by enhancing the expression of key transcription factors, FOXA1 and FOXA2, at the posttranscriptional level through m⁶A recognition. Restoring FOXA1 or FOXA2 expression mitigates the phenotypic defects observed in Ythdc1‐HKO mice. Mechanistically, YTHDC1 binds to the m⁶A regions of Foxa1 and Foxa2 mRNAs, promoting their expression. These findings reveal a mechanism by which YTHDC1 regulates hepatocyte maturation.