Iron dyshomeostasis and its neurobiological mechanisms in psychiatric disorders

Brain iron homeostasis is indispensable for sustaining central nervous system development, neural circuit stability, and core neurobiological processes including neurotransmission, mitochondrial energetics, and synaptic plasticity. Compelling clinical and preclinical evidence has established that iron dyshomeostasis represents a pervasive, convergent pathological driver of multiple psychiatric disorders, spanning anxiety, depression, schizophrenia, and neurodevelopmental and affective spectrum conditions. Nevertheless, current literature remains fragmented by disease-specific investigation, with persistent unresolved contradictions regarding regional iron deficiency versus overload in disease pathogenesis. Moreover, the cell-type- and circuit-specific mechanisms linking iron imbalance to psychiatric phenotypes, lacks systematic integration-hindering mechanistic consensus and translational advancement. In this comprehensive review, we synthesize multimodal evidence from human neuroimaging, post-mortem tissue analysis, clinical cohorts, and preclinical animal studies to delineate the distinct regulatory logics governing peripheral and cerebral iron metabolism. We systematically dissect how disrupted iron homeostasis triggers a cascade of neurobiological impairments, encompassing oxidative stress, ferroptosis, neuroinflammation, myelination defects, neurotransmitter dysfunction, and maladaptive synaptic remodeling. Synthesizing these findings, we construct a unified mechanistic framework illustrating how diverse etiological factors-genetic predisposition, chronic psychosocial stress, neuroinflammatory insult, and developmental influences-converge to drive region- and cell-specific iron perturbations and subsequent circuit dysfunction. We further summarize the translational potential and inherent limitations of existing iron-targeted intervention strategies. Collectively, this synthesis positions brain iron dyshomeostasis as a core convergent node in the pathophysiological network of psychiatric disorders, bridges basic iron neurobiology with translational neuroscience, and provides a conceptual framework and practical roadmap for biomarker discovery, mechanistic dissection, and next-generation therapeutic development in psychiatry.