AUTHOR=Ge Ziyu , Hu Yongdong , Kan Weijing , Li Lei , Xu Jiyi , Zhang Yi , Zheng Nan , Wang Gang , Du Jing 

TITLE=Lipid metabolic dysregulation-induced neuroinflammation in the pathophysiology of major depressive disorder

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1625087

DOI=10.3389/fimmu.2025.1625087

ISSN=1664-3224

ABSTRACT=Depressive disorders exhibit significant comorbidity with lipid dysregulation. Clinical observations indicate that poor lifestyle factors contribute to lipid dysregulation in depressed patients. This dysregulation disrupts gut microbiota homeostasis and endocrine balance. Mitochondria and endoplasmic reticulum, critical organelles for lipid metabolism, also show impaired homeostasis in depression, further contributing to lipid dysregulation. Such alterations activate peripheral and central immune-inflammatory responses, compromise blood-brain barrier integrity, and disrupt neuroimmune cytokine signaling. This process induces and aggravates neuroinflammation, thereby contributing to the onset and progression of depressive disorders. These disruptions in homeostasis further exacerbate lipid dysregulation. This review delineates the molecular mechanisms by which dysregulation of lipid metabolism exacerbates depressive disorders via neuroinflammatory pathways, offering critical insights into pathogenesis and therapeutic strategies.