Peptide deregulated in hypertrophic scar-1 alleviates hypertrophic scar fibrosis by targeting focal adhesion kinase and pyruvate kinase M2 and remodeling the metabolic landscape.
Peptide deregulated in hypertrophic scar-1 alleviates hypertrophic scar fibrosis by targeting focal adhesion kinase and pyruvate kinase M2 and remodeling the metabolic landscape.
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DOI：
10.1016/j.ijbiomac.2023.123809
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发表时间：
2023-02
影响因子：
8.2
通讯作者：
Jingyun Li;Yiliang Yin;Enyuan Zhang;Mang Gui;Ling Chen;Jun Li
中科院分区：
文献类型：
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作者：
Jingyun Li;Yiliang Yin;Enyuan Zhang;Mang Gui;Ling Chen;Jun Li
增生性瘢痕是一种以胶原过度沉积为特征的纤维化皮肤病。新出现的证据表明肽在纤维化相关疾病中的重要作用。在这里，我们证明，皮肤来源的内源性肽，肽失调的增生性瘢痕-1（PDHS 1），序列IATTTASAATAAAIGATPRAK，抑制细胞增殖，促进凋亡，减少细胞的比例在S期，并减少胶原蛋白的合成在增生性瘢痕成纤维细胞。此外，用PDHPS 1治疗可在兔耳模型中减轻肥大性瘢痕形成。发现PDHPS 1与粘着斑激酶（FAK）结合并降低其活性。PDHPS 1还显示与丙酮酸激酶M2（PKM 2）结合并降低其表达。用PDHPS 1处理也抑制Smad 2磷酸化。FAK的过表达挽救了由PDHPS 1处理诱导的COL 3A 1表达的降低。靶向代谢组学研究表明，PDHPS 1基因对与氨基酸合成相关的代谢进行了重编程，导致糖酵解关键中间体葡萄糖-6-磷酸和果糖-6-磷酸的减少。这些结果表明，内源性肽PDHPS 1通过靶向FAK和PKM 2并重塑代谢景观，在体外和体内抑制增生性瘢痕纤维化。总的来说，PDHPS 1治疗是一种潜在的治疗策略。
Hypertrophic scarring is a fibrotic skin disease characterized by excessive deposition of collagens. Emerging evidence has suggested important roles for peptides in fibrosis-related diseases. Here, we demonstrate that a skin-derived endogenous peptide, peptide deregulated in hypertrophic scar-1 (PDHS1), with the sequence IATTTASAATAAAIGATPRAK, inhibits cell proliferation, promotes apoptosis, decreases the proportion of cells in S phase, and decreases collagen synthesis in hypertrophic scar fibroblasts. Additionally, treatment with PDHPS1 alleviates hypertrophic scarring in a rabbit ear model. PDHPS1 was found to bind to focal adhesion kinase (FAK) and to decrease its activity. PDHPS1 was also shown to bind to pyruvate kinase M2 (PKM2) and to decreased its expression. Smad2 phosphorylation is also inhibited by treatment with PDHPS1. Overexpression of FAK rescues the decreased expression of COL3A1 induced by PDHPS1 treatment. Targeted metabolomics revealed that PDHPS1 reprogramed metabolism that related to amino acid synthesis, leading to decreases of the key glycolysis intermediates glucose-6-phosphate and fructose-6-phosphate. These results demonstrated that the endogenous peptide PDHPS1 alleviates hypertrophic scar fibrosisin vitroandin vivoby targeting FAK and PKM2 and remodeling the metabolic landscape. Overall, treatment with PDHPS1 is a potential therapeutic strategy for hypertrophic scarring.