miR-206-mediated Regulation in Depression: From Pathophysiological Mechanisms to Intranasal AntagomiR-206 Therapy

Depression is a globally prevalent mental disorder characterized by persistent low mood and cognitive deficits, with high incidence and recurrence rates, causing a heavy burden on individual health and public health systems worldwide. MicroRNAs (miRNAs), a class of single-stranded noncoding RNAs (ncRNAs) composed of 18-25 nucleotides, regulate gene expression at the posttranscriptional level by binding to the 3' UTR of target mRNAs. Due to their ability to inhibit translation and their high enrichment in brain tissue, miRNAs have become key players in depression research, with increasing evidence supporting their potential as diagnostic biomarkers and therapeutic targets for the disease. Among these miRNAs, miR-206 is considered a critical regulator of stress susceptibility and is highly expressed in brain regions associated with depression, including the hippocampus and prefrontal cortex (PFC). Numerous preclinical studies have confirmed the role of miR- 206 in stress responses. However, the precise neurobiological mechanisms involved in depression, including its regulation of neurogenesis, neuroinflammation, the gut-brain axis, and interactions with key molecules such as BDNF, remain incompletely understood. This review synthesizes the latest research progress on miR-206, focusing on its multifaceted involvement in the pathophysiology of depression. By summarizing findings on its downstream signaling pathways, tissue-specific expression patterns, and regulatory effects on antidepressant effects such as ketamine-mediated regulation, this study aims to provide new insights into the diagnosis and treatment of major depressive disorder (MDD) and offer important guidance for the development of next-generation antidepressant drugs.