p21 Inhibition Rescues Radiation‐Induced Osteogenic Dysfunction and Promotes Bone Regeneration in Osteoradionecrosis of the Jaw via the Rb–Smad2/3–Runx2 Axis

ABSTRACT Background Osteoradionecrosis of the jaw (ORNJ) is a severe radiotherapy complication with unclear molecular drivers. CDKN1A/p21 is upregulated by radiation‐induced DNA damage, but its role in ORNJ remains unknown. Methods An ORNJ mouse model was established. Single‐cell RNA‐sequencing of irradiated mandibles was analyzed and validated in vivo. Irradiated jaw bone marrow mesenchymal stem cells (JBMMSCs) were characterized. p21 was inhibited using UC2288 and siRNA. A UC2288‐loaded AlgMA hydrogel was developed for local delivery. Results Bone healing was compromised in ORNJ. Radiation induced p21 upregulation in osteogenic lineage cells, which promoted Rb dephosphorylation and aberrant Smad2/3 phosphorylation, thereby suppressing Runx2‐mediated osteogenesis. p21 inhibition reversed this cascade and restored osteogenic differentiation. Local delivery of UC2288@AlgMA significantly enhanced bone regeneration. Conclusion p21‐related signaling impairs bone healing after irradiation, and local UC2288 delivery via AlgMA hydrogels represents a viable strategy to enhance ORNJ regeneration.