FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation
Abstract Keloids are pathological scars exhibiting tumour-like aggressiveness and high recurrence rate. Here we find increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senescent fibroblasts, and enhanced expression of senescence-associated secretory phenotype gene...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07738-0 |
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| author | Yu-Xiang Kong Zhi-Shuai Li Yuan-Bo Liu Bo Pan Xin Fu Ran Xiao Li Yan |
| author_facet | Yu-Xiang Kong Zhi-Shuai Li Yuan-Bo Liu Bo Pan Xin Fu Ran Xiao Li Yan |
| author_sort | Yu-Xiang Kong |
| collection | DOAJ |
| description | Abstract Keloids are pathological scars exhibiting tumour-like aggressiveness and high recurrence rate. Here we find increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senescent fibroblasts, and enhanced expression of senescence-associated secretory phenotype genes using single-cell RNA sequencing analysis, as well as elevated p16 protein and more β-galactosidase-positive cells in keloids. The up-regulated p53-serine15 phosphorylation (p53-pS15) in keloids is identified by phosphospecific protein microarray and western blotting. We further demonstrate that a senolytic FOXO4-D-retro-inverso-isoform peptide (FOXO4-DRI) promotes apoptosis and decreases G0/G1 phase cells in pro-senescence models of keloid organ cultures and fibroblasts, accompanied with p53-pS15 nuclear exclusion. Our study indicates that upregulation of p53-pS15 and p16 maintains a persistent senescent microenvironment to promote cell cycle arrest and apoptosis resistance in keloid fibroblasts. FOXO4-DRI shows potential as a treatment targeting the senescence and apoptosis resistance, and holds promise as an approach to prevent the aggressiveness and relapse of keloids. |
| format | Article |
| id | doaj-art-001df97ec6f04bedace2897f00a3e90c |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-001df97ec6f04bedace2897f00a3e90c2025-08-20T01:56:01ZengNature PortfolioCommunications Biology2399-36422025-02-018111310.1038/s42003-025-07738-0FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylationYu-Xiang Kong0Zhi-Shuai Li1Yuan-Bo Liu2Bo Pan3Xin Fu4Ran Xiao5Li Yan6Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeResearch Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAuricular Plastic and Reconstructive Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeResearch Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeResearch Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeResearch Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Keloids are pathological scars exhibiting tumour-like aggressiveness and high recurrence rate. Here we find increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senescent fibroblasts, and enhanced expression of senescence-associated secretory phenotype genes using single-cell RNA sequencing analysis, as well as elevated p16 protein and more β-galactosidase-positive cells in keloids. The up-regulated p53-serine15 phosphorylation (p53-pS15) in keloids is identified by phosphospecific protein microarray and western blotting. We further demonstrate that a senolytic FOXO4-D-retro-inverso-isoform peptide (FOXO4-DRI) promotes apoptosis and decreases G0/G1 phase cells in pro-senescence models of keloid organ cultures and fibroblasts, accompanied with p53-pS15 nuclear exclusion. Our study indicates that upregulation of p53-pS15 and p16 maintains a persistent senescent microenvironment to promote cell cycle arrest and apoptosis resistance in keloid fibroblasts. FOXO4-DRI shows potential as a treatment targeting the senescence and apoptosis resistance, and holds promise as an approach to prevent the aggressiveness and relapse of keloids.https://doi.org/10.1038/s42003-025-07738-0 |
| spellingShingle | Yu-Xiang Kong Zhi-Shuai Li Yuan-Bo Liu Bo Pan Xin Fu Ran Xiao Li Yan FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation Communications Biology |
| title | FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation |
| title_full | FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation |
| title_fullStr | FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation |
| title_full_unstemmed | FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation |
| title_short | FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation |
| title_sort | foxo4 dri induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53 serine 15 phosphorylation |
| url | https://doi.org/10.1038/s42003-025-07738-0 |
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