Fig. 4: Hypothetical mechanism of microglial restoration through lipid droplet degradation.
From: Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases
In LDs-laden microglia, pathological LD accumulation impairs mitochondrial metabolism, nuclear-cytoplasmic transport (NCT), and DNA repair, while promoting chronic inflammation. Enforcing LDs degradation through lipolysis or lipophagy initiates a metabolic reprogramming cascade (1), leading to increased fatty acid oxidation (FAO) (2), restoration of NCT (3), and enhanced DNA damage repair (4). These changes reduce the release of pro-inflammatory mediators such as IL-1β, IL-6, IL-8, MCP1, PGE2, and reactive oxygen/nitrogen species (ROS/NOX) (5). Together, these processes break the vicious cycle of microglial dysfunction by improving bioenergetics, reducing inflammation, and restoring nuclear homeostasis. The outcome is a functional restoration of microglia from a pro-inflammatory, LDs-laden phenotype to a homeostatic state, characterized by improved phagocytosis and reduced oxidative stress. Created with Biorender.com.
