HDAC4 regulates hASC osteogenesis and bone regeneration by mediating SMAD4 via histone acetylation.

Craniofacial large bone defects possess limited self-repair capacity. This study identifies histone deacetylase 4 (HDAC4) as a key epigenetic repressor of osteogenesis in human adipose-derived stem cells. Inhibiting HDAC4, either genetically or pharmacologically with tasquinimod, enhanced histone acetylation and activates SMAD4 expression, thereby promoting bone formation. A sustained-release hydrogel delivering tasquinimod was developed and demonstrated to significantly enhance bone regeneration in critical-sized cranial and mandibular defects in mice. The findings reveal a promising localized epigenetic strategy for repairing craniofacial bone defects.