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Adipose-derived stem cells (ADSCs) play an important role in inhibiting pathological scar formation. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate the function, mechanism, and therapeutic potential of adipose-derived stem cell peptide 5 (ADSCP5), a novel peptide from adipose-derived stem cell-conditioned medium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used in vitro hypertrophic scar fibroblast, macrophage\u2013fibroblast coculture and human umbilical vein endothelial cell (HUVEC) assays, RNA sequencing, pathway analysis, peptide pull-down, molecular docking, cellular thermal shift assays, surface plasmon resonance, immunofluorescence colocalization analysis, western blotting, rescue experiments, reactive oxygen species (ROS), autophagy tests, and mitochondrial membrane potential assays and untargeted metabolomics. The efficacy of ADSCP5 was validated in rabbit and porcine scar models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In hypertrophic scar fibroblasts, ADSCP5 significantly downregulated the expression of collagen genes (COL1A1, COL1A2, and COL3A1) and actin alpha 2, smooth muscle, without affecting cell proliferation, apoptosis, or migration. Transcriptomic, enrichment, and western blot analyses confirmed that ADSCP5 reduced the protein levels of phosphorylated p65 (p-p65, NF-\u03baB subunit), p-PI3K, p-AKT, and p-mTOR. Moreover, ADSCP5 decreased IL-6 transcription. Mechanistically, ADSCP5 bound directly to pyruvate carboxylase or the NF-\u03baB subunit p50. This interaction resulted in the downregulation of PC or the upregulation of p50, ultimately inhibiting collagen expression, a finding confirmed by rescue assays. Furthermore, ADSCP5 induced ROS generation and autophagy, altered global metabolism, and modulated macrophage\u2013fibroblast crosstalk to suppress fibrosis. It also exhibited antiangiogenic effects in HUVECs. In both the rabbit and porcine scar models, ADSCP5 treatment effectively attenuated collagen deposition and scar hyperplasia, increased the number of macrophages (increased CD68), reduced angiogenesis (decreased VEGFA and CD34), and promoted autophagy (reduced p62).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, this study demonstrate that ADSCP5 alleviates hypertrophic scarring by directly binding to PC and p50, suppressing the PI3K\/AKT\/mTOR and NF-\u03baB pathways, reducing IL-6 and collagen production, promoting ROS and autophagy, and modulating metabolic, macrophage and angiogenic responses. These findings position ADSCP5 as a promising therapeutic agent for hypertrophic scar prevention and treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/burnst\/tkag040","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:49:29Z","timestamp":1780487369000},"source":"Crossref","is-referenced-by-count":0,"title":["Adipose-derived stem cell peptide 5 alleviates hypertrophic scarring through targeting pyruvate carboxylase or p50 to coordinate PI3K\/AKT\/mTOR-autophagy and NF-\u03baB\/IL-6 signaling"],"prefix":"10.1093","volume":"14","author":[{"given":"Ling","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Plastic&Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital) , 123 Tianfei Street, Mochou Road, Nanjing 210004 ,","place":["China"]},{"name":"Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated 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Medical University (Nanjing Women and Children's Healthcare Hospital) , 123 Tianfei Street, Mochou Road, Nanjing 210004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-589X","authenticated-orcid":false,"given":"Jingyun","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing Women and Children's Healthcare Institute, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital) , 123 Tianfei Street, Mochou Road, Nanjing 210004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Plastic&Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital) , 123 Tianfei Street, Mochou Road, Nanjing 210004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5419-2656","authenticated-orcid":false,"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Plastic&Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital) , 123 Tianfei Street, Mochou Road, Nanjing 210004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zezhang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , 321 Zhongshan Road, Nanjing 210008 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