Sex-divergent microRNA–mRNA regulatory networks in the dorsolateral prefrontal cortex in major depressive disorder

Post-mortem studies have identified transcriptomic alterations in major depressive disorder (MDD), but sex-specific post-transcriptional mechanisms remain poorly understood. Here, we profiled microRNAs and mRNAs in the dorsolateral prefrontal cortex of males and females with MDD, most of whom died by suicide, and sex-matched controls. We integrated these profiles with experimentally supported microRNA–target interactions, validated selected changes by RT-qPCR, and mapped targets using an independent single-nucleus transcriptomic dataset. Differentially expressed microRNAs were predominantly upregulated in males and downregulated in females (73% in each sex), and differentially expressed genes largely differed between sexes; most shared microRNAs and genes altered in both sexes changed in opposite directions. In males, microRNA-mRNA regulatory networks involved genes related to proteostasis and intracellular trafficking, and mapped mainly to excitatory neurons. In females, these networks involved genes related to metabolism and neuroendocrine-immune signaling, distributed across neuronal, glial, and vascular cells. These findings reveal sex-divergent post-transcriptional regulation in MDD and support sex-stratified biomarker and therapeutic research.