KDM8 acts as a co-regulator of transcription factor SOX2 for promoting cell pluripotency.

iPSCs have drawn significant attention for their biomedical potential, yet reprogramming remains inefficient and the underlying mechanisms are incompletely defined. KDM8, a histone demethylase, is known to play critical roles in processes such as cell-cycle regulation and embryonic development; nevertheless, its function in reprogramming has not been reported. Our investigations demonstrate that KDM8 significantly enhances the reprogramming efficiency mediated by the canonical Yamanaka factors. Remarkably, KDM8, in combination with OCT4 alone, is sufficient to reprogram somatic cells. Further analyses reveal that KDM8 facilitates reprogramming through a dual regulatory mechanism. On one hand, KDM8 leverages its canonical enzymatic activity to reduce the epigenetic barriers to iPSC formation. More importantly, KDM8 functions as a co-regulator of the transcription factor SOX2, promoting SOX2's DNA-binding affinity and transcriptional regulation of downstream pluripotency target genes. Accordingly, we propose a novel regulatory framework that uncovers novel mechanisms and functions of KDM8 in cellular reprogramming.