Oligodendrocyte lineage cells dysfunction in depression: early life stress, adolescent vulnerability and the emerging role of lipid metabolism

Depression, as a serious global public health issue, is exhibiting an increasing incidence among younger populations, particularly adolescents, who face unique diagnostic challenges and poorer prognoses. Despite extensive studies on monoaminergic dysfunction, neuroinflammation, and synaptic deficits, its pathophysiological mechanisms remain incompletely understood, particularly in relation to developmental stage-specific vulnerabilities. Oligodendrocyte (OL) lineage cells have recently emerged as potential contributors to depression pathology, not only through their myelinating roles but also via non-myelinating functions, such as metabolic support, neuroimmune interaction, and circuit modulation. Early life represents a critical development window characterized by rapid proliferation, differentiation, and lipid synthesis of oligodendrocyte precursor cells, during which these cells are highly susceptible to environmental stressors. Such developmental susceptibility may underlie the long-lasting impact of early life stress (ELS) contribute to depression risk across the lifespan. This review summarizes recent advances in understanding the myelinating and non-myelinating functions of OL lineage cells related to depression pathology, with particular emphasis on their developmental vulnerability to ELS and potential contribution of lipid metabolic dysregulation. We further review emerging pharmacological and non-pharmacological strategies targeting OL lineage cells as potential therapeutic methods.