Chemical reprogramming enables the generation of human pluripotent stem (hCiPS) cells from somatic cells using small molecules, providing a promising strategy for regenerative medicine. However, the current method is time consuming, and some cell lines from different donors are resistant to chemical induction, limiting the utility of this approach. Here, we developed a fast reprogramming system capable of generating hCiPS cells in as few as 10 days. This accelerated method enables efficient generation of hCiPS cells with a consistent 100% success rate across 15 different donors, increasing efficiency by over 20-fold within 16 days, especially for previously resistant cells. Mechanistically, we identified KAT3A/KAT3B and KAT6A as key epigenetic obstacles; suppressing these factors facilitated the transition of somatic cells to a poised state by triggering switches in the epigenome. These results highlight the superiority of this system for generating hCiPS cells, which represents a next-generation approach for manufacturing cells for further applications.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.