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PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation

Hongrui Chen1,2, Zening Huang3, Rui Chang1

  • 1Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 29, 2026
PubMed

Insights

PIK3CA mutations in facial infiltrating lipomatosis (FIL) disrupt PPT1 depalmitoylation, stabilizing P300. This drives excessive adipogenesis, offering new therapeutic targets for FIL.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Facial infiltrating lipomatosis (FIL) is driven by PIK3CA mutations, but the underlying molecular pathways are not fully understood.
  • Aberrant adipogenesis is a hallmark of FIL, leading to benign adipose overgrowth.
  • Understanding the regulation of adipogenesis in FIL is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of palmitoyl-protein thioesterase 1 (PPT1) in regulating adipogenesis driven by PIK3CA mutations in FIL.
  • To elucidate the molecular mechanisms by which PPT1 influences adipogenic gene expression and cellular fate.
  • To identify potential therapeutic targets for FIL based on the discovered signaling pathway.

Main Methods:

  • Single-cell RNA-seq, molecular dynamics simulations, and functional assays in human FIL cells and mouse models.
  • Chromatin immunoprecipitation (ChIP-qPCR), acyl-biotin exchange assays, and luciferase reporter assays.
  • RNA sequencing and ATAC sequencing to analyze gene expression and chromatin accessibility.

Main Results:

  • PIK3CA mutations were found to transcriptionally repress PPT1 expression via the PI3K-AKT-c-JUN signaling pathway.
  • Reduced PPT1 levels led to increased palmitoylation of the transcriptional coactivator P300 at C1176, stabilizing it.
  • Palmitoylation of P300 preserved its histone acetyltransferase activity by inhibiting phase separation, promoting adipogenic gene expression and excessive adipogenesis in FIL.

Conclusions:

  • A novel signaling axis involving "palmitoylation-phase separation-epigenetic regulation" controls cellular fate in FIL.
  • PPT1 and P300 are key regulators of adipogenesis in FIL and represent potential therapeutic targets.
  • This study provides critical insights into the molecular pathogenesis of FIL and opens avenues for novel treatment strategies.
Keywords:
PIK3CAadipogenesispalmitoylationphase separation

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