A cross-talk between p16High senescence and cellular reprogramming.

Cellular senescence and OSKM (Oct4, Sox2, Klf4, and Myc)-mediated reprogramming represent interconnected biological programs that both play important roles in regulating cellular plasticity. Recent studies have highlighted the role of p16-driven senescence in establishing a stable barrier to reprogramming by limiting epigenetic flexibility. Mechanistically, p16High senescent fibroblasts enforce this barrier through stress-induced and AP-1-driven epigenetic remodeling and NNMT-mediated metabolic SAM depletion, which restricts methylation-dependent chromatin remodeling in both p16High and neighboring p16Low cells via a paracrine mechanism. Conversely, clearance of p16High cells restores SAM levels and enhances cellular plasticity in neighboring cells, enabling the acquisition of totipotent-like states during reprogramming. Within p16High cells themselves, reprogramming can reverse some features of senescence, restoring more youthful cellular states under controlled conditions. Importantly, p16High cells remain highly resistant to full reprogramming, minimizing the risk of teratoma and tumor formation in vivo and making them promising target for rejuvenation strategies based on partial reprogramming. In this review, we examine the molecular interplay between p16High senescence and reprogramming, highlighting their dual roles as both barriers to and facilitators of cell fate transitions.