Identification of FOXK1 and SEMA7A as key genes associated with m6A-related programmed cell death in diabetic retinopathy.

BACKGROUND: 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 (m6A) modification. The objective of this research was to pinpoint crucial genes related to m6A-related PCD in DR using transcriptomic data, offering novel targets and a theoretical basis for the pathogenesis of DR. METHODS: In this study, transcriptomic data of DR samples and control samples were obtained from a public database. Meanwhile, m6A-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. RESULTS: 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. CONCLUSION: This study identified FOXK1 and SEMA7A as key genes in DR related to m6A-associated programmed cell death, which may provide a new direction for subsequent research on diagnosis and treatment.