The expression of the surface integrin protein CD49f characterizes astrocytes that strongly respond to pro-inflammatory stimuli and secret neurotoxic lipoparticles enriched in saturated long and very-long-chain fatty acids. Given the critical role of this astrocyte subset in neuroinflammation and neurodegeneration, models to study and modify their neurotoxic phenotype are in increasing demand. Here we propose CD49f enriched human astrocytic U373 cells as a cost- and time-effective model to evaluate the metabolic and functional changes that reactive astrocytes undergo under pro-inflammatory conditions and their epigenetic modulation by histone deacetylase inhibitors (HDACis). We confirmed by flow cytometry and qPCR analysis that U373 astrocytes constitutively express high levels of CD49f, and, similar to primary and hiPSC-derived CD49f+ astrocytes, respond to pro-inflammatory stimulation with TNFα, IL1α and C1q with increased expression of the astrocytic reactive markers vascular cell adhesion molecule 1 (VCAM1) and programmed cell death ligand 1 (PDL1), as well as of the pro-inflammatory mediators CXCL10, IL8 and IL1b. We used chromatography-mass spectrometry to study the metabolic changes that reactive astrocytes undergo, and observed that activated U373 cells accumulate the neurotoxic very-long-chain fatty acid C26:0. Further, live-imaging revealed a decreased phagocytic capacity of myelin debris upon induction of the A1-reactive state in U373 astrocytes. We found that treatment with the HDACis vorinostat and entinostat restored both metabolic and functional changes observed in the reactive astrocytes. Altogether, our data suggest that activated human U373 astrocytes provide a cost-effective easy accessible model to study and modulate the functional and metabolic changes associated with neurotoxic astrocytes.