Weihua Wang, Huajun Pan, Yashi Mi, Juvie Farol, Fei Yin
Abstract Neurodegenerative diseases are increasingly recognized as multicellular pathologies in which astrocytes serve as active determinants of disease onset and progression. Central to the regulatory role of astrocytes is the precise and dynamic control of brain lipid homeostasis. This review discusses a framework positioning astrocytic lipid metabolism as a key axis of both brain metabolic health and neurodegenerative processes. Under physiological conditions, astrocytes operate as the primary lipid metabolic hub, coordinating de novo cholesterol synthesis, APOE-mediated lipid transport, and the uptake and degradation of fatty acids. However, upon aging, chronic stress, and proteinopathies, these homeostatic programs undergo profound adaptation and remodeling. We detail how the breakdown of astrocytic lipid handling—driven by genetic risk factors such as APOE4 and manifesting as cholesterol dyshomeostasis, aberrant lipid droplet accumulation, impaired lipid turnover, and pro-inflammatory lipid signaling—transforms astrocytes into maladaptive reactive states and contributes to neurodegeneration. This metabolic rewiring not only deprives vulnerable neurons of essential metabolic and structural support but actively amplifies neuroinflammation and neurotoxicity. Finally, we consider therapeutic strategies aimed at restoring functional lipid flux and mitigating lipid-driven pathogenic signaling. By examining neurodegeneration through the lens of astrocytic lipid metabolism, we highlight novel conceptual paradigms for understanding neurodegeneration and emerging translational opportunities for disease interventions.