2. Academic Validation
  3. Acetylation-triggered degradation of MSX1 impairs palatal development

Acetylation-triggered degradation of MSX1 impairs palatal development

  • Cell Death Discov. 2026 Mar 19;12(1):156. doi: 10.1038/s41420-026-03018-w.
Li Meng # 1,  Jiawen You # 2,  Zhongyin Zhang 3,  Yucheng Jiang 3,  Yulan Liu 1,  Mingliang Zhou 4,  Junqing Ma 5 6,  Xinquan Jiang 7 8
Affiliations

Affiliations

  • 1 Department of Prosthodontics, Shanghai Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China.
  • 2 Stomatological Hospital affiliated Suzhou Vocational Health College, Suzhou, China.
  • 3 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China.
  • 4 Shanghai Stomatological Hospital, Fudan University, Shanghai, China. [email protected].
  • 5 Savaid Stomatology School, Hangzhou Medical College, Hangzhou, China. [email protected].
  • 6 Hangzhou Stomatological Hospital (Zijingang Campus), Hangzhou, China. [email protected].
  • 7 Department of Prosthodontics, Shanghai Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China. [email protected].
  • 8 Shanghai Stomatological Hospital, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41856994 DOI: 10.1038/s41420-026-03018-w
Abstract

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.

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