Herpes simplex virus type-1 (HSV-1) is a widespread human pathogen that relies on host cell pathways, including those involved in metabolism to support replication. Here, we demonstrate that de novo lipogenesis is essential for HSV-1 infectivity. Specifically, HSV-1 infection upregulates fatty acid synthase (FASN) expression, accompanied by a marked increase in lipids and a differential lipid species distribution. Conversely, silencing FASN or applying FASN inhibitors (i.e., CMS121 and C75) markedly reduces the infectivity of newly released HSV-1 virions, suggesting that, while initial replication remains unaffected, FASN is crucial for maintaining virion structure and facilitating 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. Specifically, HSV-1 infection enhanced CD36-mediated fatty acid uptake, especially in FASN-depleted cells, compensating for reduced lipogenesis. Blocking CD36 function with SSO further decreased viral infectivity, demonstrating the critical role of lipid uptake in HSV-1 life cycle. Altogether, our findings reveal how HSV-1 manipulates lipid metabolism, offering insights into its association with chronic disease and therapeutic intervention.
Copyright: © 2025 Albano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.