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This study investigated the role of palmitoyl\u2010protein thioesterase 1 (PPT1)\u2010mediated depalmitoylation in regulating aberrant adipogenesis induced by mutant\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    . Using single\u2010cell RNA\u2010seq, molecular dynamics simulations, and functional assays in primary human FIL adipose\u2010derived stem and progenitor cells (ASPCs), immortalized cell lines, and mouse models, we dissected the signaling pathway linking\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    mutation to adipogenesis. Techniques included ChIP\u2010qPCR, acyl\u2010biotin exchange assays, luciferase reporter assays, and RNA\/ATAC sequencing.\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    mutations transcriptionally repressed PPT1 via PI3K\u2010AKT\u2010c\u2010JUN signaling. Downregulated PPT1 enhanced palmitoylation of the transcriptional coactivator P300 at C1176. This modification stabilized P300 by impairing its interaction with HSC70 and subsequent chaperone\u2010mediated lysosomal degradation. Furthermore, C1176 palmitoylation inhibited P300 phase separation, thereby preserving its histone acetyltransferase activity. Sustained P300 activity promoted chromatin accessibility and expression of adipogenic genes, driving excessive adipogenesis in FIL. These findings established a novel \u201cpalmitoylation\u2010phase separation\u2010epigenetic regulation\u201d axis in cellular fate determination and revealed PPT1 and P300 as potential therapeutic targets for FIL.\n                  <\/jats:p>","DOI":"10.1002\/advs.202523139","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T20:20:52Z","timestamp":1769718052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation"],"prefix":"10.1002","volume":"13","author":[{"given":"Hongrui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Plastic &amp; Reconstructive Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Department of Laser and Aesthetic Medicine Shanghai Ninth People's Hospital 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