Xie Anni, Li Weijia, Ye Danni, Yin Yue, Wang Ran, Wang Min, Yu Renqiang
Department of Neonatology, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, 214002, People's Republic of China.
Department of Biochemistry and Molecular Biology, Franklin & Marshall College, Lancaster, PA, 17603, USA.
J Inflamm Res. 2024 Nov 29;17:10047-10064. doi: 10.2147/JIR.S495271. eCollection 2024.
Atopic dermatitis (AD) is a common pediatric skin disease, with recent studies suggesting a role for ferroptosis in its pathogenesis. Sodium propionate (SP) has shown therapeutic potential in AD, yet its mechanism, particularly regarding ferroptosis modulation, remains unclear. This study aims to explore whether SP alleviates AD by modulating ferroptosis-related pathways through bioinformatic and in vitro analyses.
We analyzed the GEO AD cohort (GSE107361). Ferroptosis-related genes was compiled from the GeneCards Database and SP-associated therapeutic target genes were obtained from Swiss Target Prediction. To explore potential biological mechanisms, we employed Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis identified key gene modules. We also established TNF-α/IFN-γ induced AD cell models using HaCat cells and collected cell samples for further experiments.
The GSVA analysis demonstrated that ferroptosis-related genes could differentiate between healthy children and those with AD. The identified module includes genes with correlated expression patterns specifically linked to AD. Analysis using three algorithms identified potential therapeutic targets of SP. We screened 51 key genes related to AD and ferroptosis, selecting cyclin-dependent kinase 1 (CDK1) and latent transforming growth factor beta binding protein 2 (LTBP2) as co-expressed genes. Machine learning identified fatty acid binding protein 4 (FABP4) as a significant gene intersection of the 51 key genes. The bioinformatics analysis results were validated through cell experiments, showing that SP treatment increased the expression of the damaged skin genes loricrin (LOR) and filaggrin (FLG).
Our study indicates that SP may alleviate AD symptoms by modulating ferroptosis through the LTBP2/FABP4 pathway.
特应性皮炎（AD）是一种常见的儿童皮肤病，近期研究表明铁死亡在其发病机制中起作用。丙酸钠（SP）已显示出对AD的治疗潜力，但其机制，特别是关于铁死亡调节方面，仍不清楚。本研究旨在通过生物信息学和体外分析，探讨SP是否通过调节铁死亡相关途径来减轻AD。
我们分析了GEO AD队列（GSE107361）。从基因卡片数据库编译铁死亡相关基因，并从瑞士靶点预测获得SP相关治疗靶点基因。为探索潜在的生物学机制，我们采用基因集变异分析（GSVA）、基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析。加权基因共表达网络分析（WGCNA）和差异表达分析确定关键基因模块。我们还使用HaCat细胞建立了TNF-α/IFN-γ诱导的AD细胞模型，并收集细胞样本进行进一步实验。
GSVA分析表明，铁死亡相关基因可区分健康儿童和AD患儿。所确定的模块包括与AD特异性相关的具有相关表达模式的基因。使用三种算法的分析确定了SP的潜在治疗靶点。我们筛选了51个与AD和铁死亡相关的关键基因，选择细胞周期蛋白依赖性激酶1（CDK1）和潜伏转化生长因子β结合蛋白2（LTBP2）作为共表达基因。机器学习确定脂肪酸结合蛋白4（FABP4）是51个关键基因的显著基因交集。通过细胞实验验证了生物信息学分析结果，表明SP处理增加了受损皮肤基因兜甲蛋白（LOR）和丝聚合蛋白（FLG）的表达。
我们的研究表明，SP可能通过LTBP2/FABP4途径调节铁死亡来减轻AD症状。
