Wang Yinmin, Wang Xiuxia, Yuan Zhaoqi, Liu Fei, Luo Xusong, Yang Jun
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; The First People's Hospital of the Lancang Lahu Autonomous County, Yunnan, China.
J Invest Dermatol. 2025 Jan;145(1):77-84.e6. doi: 10.1016/j.jid.2024.04.023. Epub 2024 May 24.
Keloids are a skin fibrosis disease characterized by troublesome symptoms, a varying degree of recurrence and inevitable side effects from treatments. Thus, identifying their drug targets is necessary. A 2-sample Mendelian randomization analysis was conducted using proteins from the intersection of the deCODE database and "The Druggable Genome and Support for Target Identification and Validation in Drug Development" as the exposure variable. The outcome variable was based on recently published GWAS of keloids. Summary data-based Mendelian randomization and colocalization analysis was employed to distinguish pleiotropy from linkage. Candidate targets underwent drug target analysis. The primary findings were validated through single-cell RNA-sequencing data, Western Blot and immunofluorescence staining on keloids. Seven proteins were identified as potential drug targets for keloids. Among these proteins, Hedgehog-interacting protein, neurotrimin [NTM], KLKB1, and CRIPTO showed positive correlations with keloids, while PLXNC1, SCG3 and PDGFD exhibited negative correlations. Combined with the single-cell RNA-sequencing data, NTM, PLXNC1, and PDGFD were found highly expressed in the fibroblasts. NTM showed a significant increase in keloids as compared to normal scars. In accordance with the analysis, higher levels of protein expression of NTM in keloids compared to normal skin was observed. The identified proteins may be appealing drug targets for keloids treatment with a special emphasis on NTM.
瘢痕疙瘩是一种皮肤纤维化疾病，其特征为症状棘手、复发程度各异且治疗不可避免地会产生副作用。因此，确定其药物靶点很有必要。利用来自deCODE数据库与《药物基因组及药物研发中靶点鉴定与验证的支持》交集的蛋白质作为暴露变量，进行了双样本孟德尔随机化分析。结局变量基于最近发表的瘢痕疙瘩全基因组关联研究（GWAS）。采用基于汇总数据的孟德尔随机化和共定位分析来区分多效性与连锁。对候选靶点进行了药物靶点分析。通过瘢痕疙瘩的单细胞RNA测序数据、蛋白质免疫印迹和免疫荧光染色对主要研究结果进行了验证。七种蛋白质被确定为瘢痕疙瘩的潜在药物靶点。在这些蛋白质中，刺猬因子相互作用蛋白、神经调节素[NTM]、激肽释放酶B1（KLKB1）和CRIPTO与瘢痕疙瘩呈正相关，而血小板内皮细胞黏附分子1（PLXNC1）、分泌粒蛋白III（SCG3）和血小板衍生生长因子D（PDGFD）呈负相关。结合单细胞RNA测序数据，发现NTM、PLXNC1和PDGFD在成纤维细胞中高表达。与正常瘢痕相比，瘢痕疙瘩中的NTM显著增加。根据分析，与正常皮肤相比，瘢痕疙瘩中NTM的蛋白质表达水平更高。所确定的蛋白质可能是瘢痕疙瘩治疗有吸引力的药物靶点，尤其要重点关注NTM。
