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Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid\u2010binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co\u2010culture model, we examined the effect of FA overload and its impact on astrocyte\u2013motor neuron interaction. LD accumulation was tightly coupled with an NF\u2010\u03baB\u2010driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS\u2010linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte\u2013neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.<\/jats:p>","DOI":"10.1002\/glia.70136","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T16:26:03Z","timestamp":1767716763000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lactate Dehydrogenase Inhibition Reverts the Fatty Acid\u2010Induced Neurotoxic Phenotype of Astrocytes"],"prefix":"10.1002","volume":"74","author":[{"given":"Daniel","family":"Esteve","sequence":"first","affiliation":[{"name":"Department of Neurology University of Wisconsin\u2010Madison  Madison Wisconsin 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