Study summary · research use only
FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study, using keloid tissue and fibroblast/organ cultures (species not specified in the abstract), examined senescence and apoptosis pathways in keloid scars. Single-cell RNA sequencing showed an increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senescent fibroblasts, along with elevated senescence-associated secretory phenotype gene expression, elevated p16 protein, and more β-galactosidase-positive cells in keloids. Phosphospecific protein microarray and western blotting identified upregulated p53-serine15 phosphorylation (p53-pS15) in keloids. The senolytic peptide FOXO4-D-retro-inverso-isoform (FOXO4-DRI) was associated with increased apoptosis and decreased G0/G1 phase cells in pro-senescence keloid organ cultures and fibroblasts, along with nuclear exclusion of p53-pS15. The authors describe FOXO4-DRI as a candidate approach targeting senescence and apoptosis resistance in keloids.
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.
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