The Impact of Fatty Acid Synthase on HSV-1 Infectivity Unveils the Key Interconnection with Alzheimer’s Disease

Herpes simplex virus type-1 (HSV-1) is a widespread human pathogen that relies on host metabolism to favor its replication. Here, we demonstrated that de novo lipogenesis is essential for HSV-1 infectivity. Particularly, HSV-1 infection upregulates fatty acid synthase (FASN) expression, accompanied by a marked increase in lipids concentration and a differential lipid species distribution. Conversely, silencing FASN or using FASN inhibitors CMS121 and C75 reduces viral infectivity, affecting virion structure and entry into host cells. Additionally, we show that a source of lipid-rich external factors provided by fetal bovine serum significantly increases HSV-1 infectivity. Lastly, in a 3D tissue culture model of herpesvirus-induced Alzheimer’s disease (AD), both CMS121 and C75 display a potent inhibitory effect on Aß-like plaque formation, linking HSV-1-mediated lipid metabolism dysregulation to AD etiopathogenesis. Altogether, our findings reveal how HSV-1 manipulates lipid metabolism, offering insights into its association with AD and highlighting potential therapeutic targets.