Exposure to PAMP (LPS) or DAMP (HMGB1) in the presence of microglia induces pathological remodeling in astrocytes. Pathological remodeling involves epigenetic chromatin changes that repress homeostatic astroglial genes and activate a proinflammatory response (Cuautle et al., J. Neurochem. 2024). Pathologically remodeled astrocytes induce neurodegeneration and localize in the core of ischemic or traumatic brain lesions, as well as in animals exposed to status epilepticus (SE). Controlling the astroglial pathological remodeling and the proinflammatory burst is mandatory to improve neuroprotection. For that purpose, we tested the repurposed drugs losartan and resveratrol. Primary astrocytes were exposed to 500 ng/ml DAMP HMGB1 for 18h, and then we treated the cultures with losartan (1-10 μM) or resveratrol (10-100 μM). Glycyrrhizin was used as an HMGB1 antagonist. Exposure to HMGB1 induced NF-κB activation, astroglial DNA hypermethylation, increased expression of pathological marker MAFG and proinflammatory IL1B and IL6, and repressed homeostatic genes Kir4.1, GLT-1 and GS. Both Losartan and Resveratrol attenuated NF-κB activation and hypermethylation, restored GS levels, and reduced the ratio of MAFG+ nuclei (p<0.05). Losartan also restored the expression of Kir4.1, GLT-1 and GS and normalized IL-1β and IL-6 expression (p<0.05). These findings indicate that Losartan is a promising candidate to modulate astroglial pathological remodeling, justifying the future in vivo studies.