Astrocytic Lipid Dysregulation in Amyotrophic Lateral Sclerosis

Abstract Although amyotrophic lateral sclerosis (ALS) has traditionally been viewed as a motor neuron-centered disease manifesting by muscle wasting and weakness, growing evidence indicates that disease progression is strongly influenced by interactions between motor neurons and surrounding glial cells. Astrocytes are major regulators of lipid metabolism in the brain, managing cholesterol synthesis, fatty acid detoxification, lipid trafficking and storage, and redox balance. Neurons, which have limited lipid-handling capacity, rely on astrocytes to maintain a safe lipid environment. In addition to their well-established roles in neurotransmitter recycling, metabolic support, excitotoxicity, and blood–brain barrier maintenance, astrocytes contribute to ALS through multiple pathogenic mechanisms. This review focuses specifically on disturbances in lipid metabolism, an emerging aspect of astrocyte biology that has received comparatively less attention. Evidence from human neuropathology, lipidomics, genetics, and ALS models suggests that altered astrocytic lipid homeostasis contributes to motor neuron vulnerability and disease progression. Altered cholesterol metabolism, impaired peroxisomal function, defective lipid droplet dynamics, disrupted sphingolipid homeostasis, and compromised metabolic support have been linked to key disease processes, including TDP-43 pathology, mitochondrial and lysosomal dysfunction, excitotoxicity, oxidative stress, and neuroinflammation. Rather than representing a single initiating mechanism, astrocytic lipid dysregulation may constitute a convergent amplifying node through which diverse ALS-associated insults modify the neuronal microenvironment and increase vulnerability to degeneration. The contribution of astrocytic lipid dysregulation to ALS therefore provides a framework for understanding how metabolic disturbances may amplify motor neuron injury and disease progression, while identifying emerging opportunities to therapeutically target these pathways. Graphical Abstract Astrocytes are the principal regulators of lipid homeostasis in the central nervous system, and mounting evidence implicates disruption of these pathways as a key contributor to amyotrophic lateral sclerosis pathogenesis. This review examines current knowledge of astrocyte lipid metabolism, integrating findings from genetics, lipidomics, and human stem cell models to highlight emerging therapeutic opportunities targeting glial lipid biology. Created with BioRender.com.