Acetylation-Triggered Degradation of MSX1 Impairs Palatal Development

Non-syndromic cleft palate (NSCP), a prevalent congenital disorder, arises from dysregulated embryonic palatal fusion, but the posttranslational modifications (PTMs) driving this process remain poorly understood. Here, we identify lysine acetylation as a critical MSX1 proteostasis switch governing 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 NSCP models, SIRT1 suppression drives MSX1 hyperacetylation, accelerating proteasomal degradation and culminating in EPM apoptosis. Strikingly, transcriptomic profiling revealed acetylation's exclusive proteostatic role, decoupling MSX1's structural stability from transcriptional activity—a paradigm distinct from classical PTM mechanisms during development. Lentivirus-mediated delivery of 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 druggable target in NSCP, redefining PTM regulation as a central etiological factor in genetic disorders.