LAUSR

Neurodevelopmental impairment due to hypoxic–ischemic brain damage (HIBD) lacks effective biomarkers and therapeutic targets. Based on some cues from published papers, extracellular serine/threonine protein kinase FAM20C was speculated to play a crucial role in the neurodevelopmental impairment of HIBD. In this study, FAM20C was found suppressed in the ischemic hippocampal tissue of HIBD. The inhibition of FAM20C caused by HIBD affected cell differentiation and subsequently caused cognitive impairment. KAP1 was identified as a kinase substrate of FAM20C in the central nervous system. The regulation of the YTHDC1‐NCL‐KAP1‐LINE1 RNA complex by FAM20C was mediated through KAP1 phosphorylation and LINE1 RNA m6A. These alterations consequently modulated the establishment of the H3K9me3 modification on LINE1 DNA, thereby resulting in neuronal differentiation. Furthermore, E2F4, identified as a transcription factor, regulated FAM20C in HIBD. This research has clarified the novel association between FAM20C and HIBD, laying the foundation for innovative diagnostic and therapeutic strategies to counteract neurodevelopmental disruptions arising from neonatal hypoxic–ischemic encephalopathy (HIE).