Does LCN2 Play a Critical Role in the Pathogenesis of Depression?

Depression, a leading global cause of disability, is increasingly recognized as a disorder involving immune-inflammatory dysregulation. Lipocalin-2 (LCN2), a secreted glycoprotein of the lipocalin family, has emerged as a critical mediator of neuroinflammation and a potential link between peripheral and central inflammatory processes in depression. This review synthesizes current evidence on LCN2's roles in depression pathophysiology, highlighting its dual pro- and anti-inflammatory functions, regulation of blood-brain barrier permeability, and interactions with astrocytes, microglia, neurons, and neutrophils. LCN2 promotes neuroinflammation via nuclear factor-kappa-B (NF-κB), Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), and NOD-like receptor pyrin domain-containing 3 (NLRP3) pathways while impairing neurogenesis and synaptic plasticity. Clinical studies associate elevated circulating LCN2 with depression severity, poor treatment response, and sex-specific comorbidities, underscoring its diagnostic potential. Therapeutic strategies targeting LCN2-including anti-inflammatory agents, iron chelators, and nanoparticle-based delivery-hold promise but require further development. By integrating preclinical and clinical findings, this review proposes LCN2 as a promising theragnostic target in depression, potentially bridging neuroimmune mechanisms with novel treatment paradigms.