Table_1_ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism.xlsx

BackgroundPsoriasis is an immune-related skin disease notable for its chronic inflammation of the entire system. Alzheimer’s disease (AD) is more prevalent in psoriasis than in the general population. Immune-mediated pathophysiologic processes may link these two diseases, but the mechanism is still unclear. This article aimed to explore potential molecular mechanisms in psoriasis and AD.
MethodsGene expression profiling data of psoriasis and AD were acquired in the Gene Expression Omnibus (GEO) database. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were first applied in two datasets. Differentially expressed genes (DEGs) of two diseases were identified, and common DEGs were selected. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to explore common biological pathways. Signature transcription factors (STFs) were identified and their diagnostic values was calculated by receiver operating characteristic (ROC) curve analysis in the exploration cohort and verified in the validation cohort. The expression levels of STFs were further investigated in the validation cohort and the GTEx Portal Database. Additionally, four kinds of interaction analysis were performed: correlation analysis among STFs, gene-gene, chemical-protein, and protein-ligand interaction analyses. In the end, we predicted the transcription factor that potentially regulates STFs.
ResultsBiosynthesis and metabolic pathways were enriched in GSEA analysis. In ssGSEA analysis, most immunoreaction gene lists exhibited differential enrichment in psoriasis cases, whereas three receptor-related gene lists did in AD. The KEGG analysis of common DEGs redetermined inflammatory and metabolic pathways essential in both diseases. 5 STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) were screened from common DEGs. The ROC analysis indicated that all STFs have diagnostic values in two diseases, especially ZFPM2. The correlation analysis, gene-gene, chemical-protein, and protein-ligand interaction analyses suggested that STFs interplay and involve inflammation and aberrant metabolism. Eventually, ZNF384 was the predicted transcription factor regulating PPARG, ZNF415, HLX, and ANHX.
ConclusionsThe STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) may increase the morbidity rate of AD in psoriasis by initiating a positive feedback loop of excessive inflammation and metabolic disorders. ZNF384 is a potential therapeutic target for psoriasis and AD by regulating PPARG, ZNF415, HLX, and ANHX.

背景：银屑病（Psoriasis）是一种以全身慢性炎症为显著特征的免疫相关性皮肤病。阿尔茨海默病（Alzheimer’s Disease, AD）在银屑病人群中的患病率高于普通人群。免疫介导的病理生理过程或为二者的关联纽带，但具体机制仍未明确。本研究旨在探讨银屑病与AD潜在的分子机制。
方法：从基因表达综合数据库（Gene Expression Omnibus, GEO）中获取银屑病与AD的基因表达谱数据。首先对两个数据集分别进行基因集富集分析（Gene Set Enrichment Analysis, GSEA）及单样本基因集富集分析（single-sample GSEA, ssGSEA）。识别两种疾病的差异表达基因（Differentially Expressed Genes, DEGs），并筛选二者的共同差异表达基因。通过京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析，探究共同的生物学通路。从共同DEGs中筛选特征性转录因子（Signature Transcription Factors, STFs），并在探索队列中通过受试者工作特征（Receiver Operating Characteristic, ROC）曲线分析计算其诊断价值，随后在验证队列中进行验证。进一步在验证队列及GTEx门户数据库（GTEx Portal Database）中探究STFs的表达水平。此外，还开展了四类交互分析：STFs之间的相关性分析、基因-基因相互作用分析、化学物-蛋白质相互作用分析以及蛋白质-配体相互作用分析。最终，预测潜在调控STFs的转录因子。
结果：GSEA分析结果显示，生物合成与代谢通路显著富集。ssGSEA分析结果表明，多数免疫反应基因集在银屑病患者中呈现差异富集，而三类受体相关基因集在AD患者中呈现差异富集。对共同DEGs的KEGG通路富集分析再次证实，炎症与代谢通路是两种疾病共有的核心通路。从共同DEGs中筛选得到5个STFs：PPARG、ZFPM2、ZNF415、HLX及ANHX。ROC曲线分析显示，所有STFs在两种疾病中均具有诊断价值，其中ZFPM2的诊断效能尤为突出。相关性分析、基因-基因相互作用分析、化学物-蛋白质相互作用分析及蛋白质-配体相互作用分析结果表明，STFs之间存在相互调控作用，且参与炎症反应与代谢异常过程。最终，预测得到调控PPARG、ZNF415、HLX及ANHX的转录因子为ZNF384。
结论：STFs（PPARG、ZFPM2、ZNF415、HLX及ANHX）可能通过启动过度炎症与代谢紊乱的正反馈环路，升高银屑病患者罹患AD的风险。ZNF384通过调控上述4个STFs，有望成为银屑病与AD的潜在治疗靶点。