NANOGNB (NANOG neighbor homeobox) is a divergent homeobox gene encoding a DNA-binding transcription factor that functions in early embryonic development. NANOGNB is an extremely divergent duplicate of NANOG that arose through gene duplication and radical sequence divergence in the mammalian lineage, sharing only 20% homeodomain identity with NANOG 1. Unlike NANOG, which maintains pluripotency throughout pre-implantation development, NANOGNB expression is temporally restricted to the 8-cell and morula stages, preceding blastocyst formation in human and bovine embryos 1. When ectopically expressed, NANOGNB downregulates genes showing expression pulses at the 8-cell stage, suggesting complementary developmental roles to NANOG 1. NANOGNB is identified as a key gene involved in embryonic genome activation and its dysregulation contributes to early embryonic arrest (EEA), a critical problem affecting 40% of infertile patients in assisted reproductive technology 2. Additionally, NANOGNB mutations have been identified as potential neoantigen sources in multifocal lung adenocarcinoma, with NANOGNB-encoded neopeptides demonstrating immunogenicity in promoting CD8+ T cell responses 3. Notably, NANOGNB has been lost in the mouse evolutionary lineage but retained in humans, indicating its specific importance in primate development 4.