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Melatonin, a key regulator of circadian rhythms and sleep-wake cycles, is implicated in the pathophysiology of major depressive disorder (MDD). Emerging evidence supports its anti-inflammatory, cytoprotective, and neuroprotective roles, including promotion of neuroplasticity. This study aims to investigate alterations in serum melatonin, interleukin-6 (IL-6), and brain-derived neurotrophic factor (BDNF) levels in first-episode MDD patients, and explores their clinical correlations. A total of 74 first-episode patients diagnosed with MDD and 72 healthy controls were enrolled in this study. The severity of depressive symptoms was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24). All blood samples were collected in the morning, and serum levels of melatonin, IL-6, and BDNF were quantified via enzyme-linked immunosorbent assay (ELISA). Baseline serum concentrations of melatonin, IL-6, and BDNF were compared between the MDD group and the control group. Additionally, the discriminative ability of these biomarkers (melatonin, IL-6, and BDNF) in distinguishing MDD patients from healthy controls was evaluated using receiver operating characteristic (ROC) curve analysis. Pearson correlation analysis or Spearman's rank correlation analysis was performed to explore the relationships between serum melatonin levels and clinical disease severity, as well as with IL-6 and BDNF levels, in patients with MDD. Compared with the control group, the MDD group showed significantly higher serum levels of melatonin (Z = -3.861, P < 0.001) and IL-6 (Z = -4.240, P < 0.001), but significantly lower serum BDNF levels (t = 9.537, P < 0.001). Moreover, the combined panel of BDNF, IL-6, and melatonin achieved high accuracy in distinguishing MDD patients from healthy controls, with an area under the curve (AUC) of 0.905. Additionally, no significant correlations were found between serum melatonin levels and clinical disease severity (assessed by HAMD-24 scores), IL-6 levels, or BDNF levels in MDD patients (all P > 0.05). These findings suggest that dysregulation of melatonin, IL-6, and BDNF may contribute to the pathophysiology of first-episode MDD, with their combined measurement offering strong diagnostic potential. Show less

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition characterized by persistent low mood, affecting approximately 322 million individuals worldwide. With a staggering 15% mortality rate due to suicide among patients, MDD represents a critical global health challenge. Emerging evidence implicates microRNAs (miRNAs) in the pathogenesis of neuropsychiatric disorders; however, the role of miR-146a-3p in MDD-particularly its mechanistic involvement and potential as a diagnostic biomarker-remains unexplored. In this study, we integrated multi-database bioinformatics analyses with experimental validation to identify miR-146a-3p as a key regulator of MDD progression. Our computational screening revealed miR-146a-3p as a putative risk-associated non-coding RNA, alongside brain-derived neurotrophic factor (BDNF), a well-established MDD susceptibility gene. In vivo studies demonstrated a significant upregulation of miR-146a-3p and concurrent downregulation of BDNF in MDD model mice. Further bioinformatic predictions and dual-luciferase reporter assays confirmed a direct interaction between miR-146a-3p and BDNF mRNA, leading to post-transcriptional suppression of BDNF expression. Mechanistically, miR-146a-3p overexpression impaired synaptic plasticity, as evidenced by reduced levels of key synaptic proteins such as postsynaptic density protein 95 (PSD95) and synapsin (SYN-1), while in vitro transfection experiments validated its negative regulation of BDNF. Critically, intranasal delivery of a miR-146a-3p antagomir or exogenous BDNF protein rescued depressive-like behaviors in murine models, as assessed by open-field, forced swim, and tail suspension tests. These interventions restored synaptic protein expression and ameliorated behavioral deficits, suggesting a therapeutic avenue for MDD. Our findings establish miR-146a-3p as a pivotal epigenetic modulator of MDD pathogenesis, acting through direct suppression of BDNF-dependent synaptic plasticity. The reversibility of this pathway via antagomir inhibition highlights miR-146a-3p's dual potential as both a diagnostic biomarker and a therapeutic target. This study provides foundational insights for developing miRNA-based interventions in mood disorders. Show less