Delicate inhibition of NFκB/RELA circuitry facilitates efficient transition towards ground-state pluripotency in human
- Luqin Wang
- Lizhan Xiao
- Gaoyang Zou
- Huiping Mao
- Shihao Zhang
- Qiusheng Yang
- Chunkou Yin
- Jiani Wan
- Manish Kumar
- Haokaifeng Wu
- Haoxian Wang
- Xiaoli Zhang
- Lihua Zeng
- Chunhua Zhou
- Shengyong Yu
- Yi Li
- Lingling Zheng
- Yuliang Liu
- Baojian Liao
- Zhen Zhang
- Jing Liu
2026-07-07
Rebuilding human naïve pluripotency from primed stem cells is essential for generating pre-implantation epiblast-like cells, a key source for regenerative medicine. Here we present a defined, feeder-free protocol that efficiently converts primed human pluripotent stem cells (hPSCs) to a naïve-like state within 12 days. Integrated ATAC-seq, RNA-seq and miRNA-seq analyses reveal a rapid chromatin rewiring marked by increased accessibility at OCT/KLF motifs, closure at ZIC/RFX/NFκB sites, upregulation of miR-372/373 and miR-182/183, and downregulation of miR-302 and miR-363/106 clusters. Functional assays demonstrate that the inflammatory transcription factor NFκB/RELA blocks naïve induction by activating peri-implantation barrier genes, including IKBKE and VEGFR1. Conversely, enforced miR-372/373 expression accelerates conversion by directly targeting RELA. These data delineate an NFκB/RELA axis that orchestrates the epigenetic switch to human naïve pluripotency, offering a tractable framework for studying early human development and advancing cell-based therapies.