Microglial lipid metabolic reprogramming in neuroinflammation

Abstract

Abnormal microglial activation is a key driver of the neuroinflammatory cascade. Recent studies have shown that lipid metabolic reprogramming regulates microglial polarization and inflammatory function in a spatiotemporally specific manner. The acute phase is characterized primarily by adaptive lipid droplet formation and enhanced fatty acid oxidation, whereas the chronic phase shifts toward pathological lipid droplet accumulation, increased lipid synthesis, and impaired lipophagy. In addition, glial cells in different brain regions vary in their lipid-processing capacity and susceptibility to pathology. Previous reviews have largely focused on individual lipid-related phenomena and have not systematically summarized the spatiotemporal patterns of lipid metabolic reprogramming or potential intervention strategies. Taking a three-dimensional perspective “temporal stage, subcellular organelle, and brain region”, this review examines the dynamic characteristics of lipid metabolic reprogramming in microglia during neuroinflammation, the mechanisms underlying imbalances in interactions between subcellular organelles, and region-specific patterns. It also summarizes therapeutic strategies, including staged pharmacological interventions targeting temporal regulation, lipid metabolism, lipid clearance, and pathological effector mechanisms, as well as dietary and magnetic approaches to indirectly regulate lipid metabolism.