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Abstract
Embryonic stem cells (ESCs) maintain pluripotency through core factors such as Nanog, yet downstream epigenetic mechanisms remain unclear. This study identifies Kdm5b, an H3K4me3 demethylase, as a direct Nanog target essential for ESC self-renewal. Kdm5b overexpression sustains pluripotency without LIF and enhances reprogramming efficiency, while knockdown impairs proliferation. Genome-wide analyses reveal KDM5B occupies active intragenic regions, interacting with MRG15 and NSD3 to repress cryptic transcription and promote elongation. KDM5B also associates with DNA replication machinery, reinforcing cell cycle control. These findings uncover KDM5B as a key epigenetic regulator of pluripotency and a potential therapeutic target in cancer.