{“_”：“确定FOXK1和SEMA7A是与糖尿病视网膜病变中mA相关程序性细胞死亡相关的关键基因。”，“sup”：[“6”]}

摘要(中文译文)

糖尿病视网膜病变（DR）是糖尿病一种严重的微血管并发症，其发病机制复杂，与程序性细胞死亡（PCD）以及N6-甲基腺苷（m⁶A）修饰密切相关。本研究旨在利用转录组数据筛选DR中与m⁶A相关PCD的关键基因，为DR的发病机制提供新靶点和理论依据。本研究从公共数据库获取DR样本和对照样本的转录组数据，同时从文献中检索m⁶A和PCD相关基因。通过差异表达分析和相关性分析鉴定候选基因。利用构建的蛋白质-蛋白质相互作用（PPI）网络，采用机器学习算法筛选特征基因，并对这些基因进行表达验证以确定关键基因。随后构建预测列线图并评估其性能。进行富集分析和免疫浸润分析。最后，构建分子调控网络并进行分子对接。初步鉴定出DR与对照样本之间的3，716个差异表达基因（DRDEGs）。通过将DRDEGs与PCD相关基因及m⁶A相关差异表达基因取交集，并进行Spearman相关性分析，鉴定出58个候选基因。随后，通过PPI、机器学习和表达分析，确定叉头框K1（FOXK1）和Semaphorin 7A（SEMA7A）为关键基因。此外，这两个关键基因构建了一个准确性良好的DR诊断列线图。GSEA揭示了它们在DR发病机制中的关键作用。此外，免疫浸润分析突出了免疫失调在DR中的参与。构建的TF-mRNA-miRNA调控网络包含2个关键基因、14个转录因子和12个miRNA（如BRCA1-FOXK1-mmu-miR-7234-3p）。分子对接显示地西他滨等药物与FOXK1结合良好，值得进一步实验研究其治疗效果。本研究确定了FOXK1和SEMA7A是与m⁶A相关程序性细胞死亡相关的DR关键基因，可能为后续诊断和治疗研究提供新方向。

Abstract

Diabetic retinopathy (DR), a serious microvascular complication of diabetes, has a complex pathogenic mechanism that is intricately linked to programmed cell death (PCD) and also to N6-methyladenosine (mA) modification. The objective of this research was to pinpoint crucial genes related to mA-related PCD in DR using transcriptomic data, offering novel targets and a theoretical basis for the pathogenesis of DR. In this study, transcriptomic data of DR samples and control samples were obtained from a public database. Meanwhile, mA-and PCD-related genes were retrieved from the literature. Candidate genes were identified via differential expression and correlation analyses. Using constructed protein-protein interaction (PPI) networks, a machine learning algorithms screened for feature genes, which underwent expression validation to determine key genes. A predictive nomogram was subsequently developed and its performance evaluated. Enrichment analysis, along with immune infiltration analysis were carried out. Finally, molecular regulatory networks and molecular docking was performed. Initially, 3,716 differentially expressed genes between DR and control samples (DRDEGs) were identified. By intersecting DRDEGs with PCD-related genes and m⁶A-related differentially expressed genes, followed by Spearman correlation analysis, 58 candidate genes were identified. Subsequently, Forkhead box K1 (FOXK1) and Semaphorin 7 A (SEMA7A) were identified as key genes through PPI, machine learning, and expression analyses. Furthermore, the two key genes constructed a well accurate nomogram for DR diagnosis. GSEA revealed their critical roles in DR pathogenesis. Moreover, immune infiltration analysis highlighted the involvement of immune dysregulation in DR. The constructed TF-mRNA-miRNA regulatory network contained 2 key genes, 14 transcription factors, and 12 miRNAs (e.g. BRCA1-FOXK1-mmu-miR-7234-3p). Molecular docking showed that decitabine and other drugs bound well to FOXK1,warranting further experimental investigation into their therapeutic efficacy. This study identified FOXK1 and SEMA7A as key genes in DR related to mA-associated programmed cell death, which may provide a new direction for subsequent research on diagnosis and treatment.

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