Acetylation-triggered degradation of MSX1 impairs palatal development

Cleft palate, a prevalent congenital disorder, arises from dysregulated embryonic palatal fusion, but the posttranslational modifications (PTMs) driving this process remain poorly understood. Here, we report that lysine acetylation is a critical MSX1 proteostasis switch that governs embryonic palatal mesenchymal (EPM) cell survival. We demonstrate in vitro and in vivo that MSX1 protein stability regulation by deacetylase SIRT1-catalyzed acetylation underlies EPM apoptosis and palatal fusion. In atRA-induced cleft palate models, SIRT1 suppression drives MSX1 hyperacetylation, accelerating proteasomal degradation and culminating in EPM apoptosis. Strikingly, transcriptomic profiling revealed the exclusive proteostatic role of acetylation, indicating that MSX1's structural stability differs from its transcriptional activity-a paradigm distinct from that of classic PTM mechanisms during development. Lentivirus-mediated delivery of the deacetylase SIRT1 or the deacetylation mimic MSX1 K139R significantly reduced cleft severity, indicating its preventive and therapeutic potential in humans. Our work establishes the MSX1 acetylation as both a pathogenic driver and a druggable target in cleft palate, redefining PTM regulation as a central etiological factor in genetic disorders.