Targeting HSV-1 through FASN inhibitors: implications for Alzheimer's Disease

Herpes simplex virus type-1 (HSV-1) relies on host metabolic pathways for replication, posing challenges for antiviral strategies. Due to its neuroinvasive and neurotoxic nature, HSV-1 has been linked to neurodegenerative diseases, including Alzheimer's disease (AD). This study investigates the relationship between HSV-1 infection and cellular metabolism to develop effective antiviral interventions and identify potential AD prevention targets. Using SH-SYSY neuronal-like cells infected with HSV-1, we established an in vitro model of HSV-1-associated neuronal pathologies. Cells were treated with fatty acid synthase (FASN) inhibitors (CMS121, C75) to evaluate their antiviral effects. Moreover, FASN gene expression was silenced using specific short hairpin RNA to rule out off-target effects. The impact of FASN inhibitors on Aß-like plaque formation was assessed using a 3D tissue culture model simulating herpesvirus-induced AD. HSV-1 infection altered lipid levels and increased FASN expression, affecting viral infectivity and host-cell interactions. CMS121 and C75 significantly reduced HSV-1 infectivity and inhibited Aß-like plaque formation in the 3D AD model, suggesting a link between HSV-1-mediated lipid dysregulation and AD pathology. These results highlight the potential of FASN inhibitors as promising antiviral agents targeting lipid metabolism in HSV-1 infection and AD. Our findings demonstrate the efficacy of FASN inhibitors, CMS121 and C75, in reducing HSV-1 infectivity and inhibiting Aß-like plaque formation. This suggests a novel antiviral approach, highlighting lipid metabolism as a therapeutic target for both HSV-1 infection and AD. Future research should focus on elucidating the mechanisms and exploring the clinical potential of these compounds.