Integrative methylation and <scp>miRNA</scp> dysregulation in <scp>dlPFC</scp> reveal distinct molecular signatures of suicide and non‐suicide subtypes in major depressive disorder

Aim Major depressive disorder (MDD) is a leading cause of disability and carries a high risk of suicide. MicroRNAs (miRNAs) are epigenetic regulators implicated in MDD and can be regulated by DNA methylation, potentially reshaping downstream gene networks. We investigated methylation‐linked miRNA dysregulation and explored whether these changes are specifically associated with suicide among MDD patients. Methods Genome‐wide DNA methylation profiling of the dorsolateral prefrontal cortex from 15 MDD patients who died by suicide (MDD+S), 17 MDD patients who died from causes other than suicide (MDD−S), and 16 controls (C) using the Illumina 850K MethylationEPIC array was integrated with small RNA sequencing‐based miRNA quantification to identify miRNA‐associated differentially methylated probes (DMPs), link methylation to miRNA expression, and infer downstream targets and pathways. Results Differential methylation analysis ( P ≤ 0.05) revealed 139 miRNA‐linked DMPs in C vs. MDD+/−S, 135 in C vs. MDD−S, 179 in C vs. MDD+S, and the highest in MDD+S vs. MDD−S (235). CpG‐miRNA pairing (within 1500kb promoter) followed by Spearman correlation identified inverse associations between CpG β values and miRNA expression, with the most consistent signals in suicide‐status‐stratified subsets, including cg06341821‐hsa‐miR‐574‐3p and cg25451306‐hsa‐miR‐2110 in MDD+S‐related contrasts, and cg06179179‐hsa‐miR‐595 in MDD−S‐related contrasts. High‐confidence target prediction and ClueGO enrichment indicated distinct biology: miR‐595 target genes in MDD−S were enriched for interferon/innate immune signaling, whereas miR‐2110 target genes in MDD+S were enriched for ligand‐gated ion channel activity and synaptic/receptor signaling. Conclusion This integrated approach identifies methylation‐regulated miRNA pathways that may play key roles in the molecular pathogenesis of MDD and suicide.