Targeting a host acidic lipase as a strategy to counteract West Nile virus: implications in replication.

West Nile virus (WNV) is a neurotropic flavivirus endemic in many regions of the world, representing a persistent global health concern. Although most WNV infections are asymptomatic or mild, the neuroinvasive form can cause severe inflammatory diseases that can lead to meningitis and encephalitis, with no specific antivirals or vaccines currently available for humans. Like other flaviviruses, WNV profoundly remodels host lipid metabolism to support its replication and evade immune responses. These viruses boost lipogenesys to shield the replication factories against the cellular defenses. In a previous work we showed that a key enzyme involved in lipid disruption, N- acylethanolamine acid amidase (NAAA), plays a crucial role in the replication of Zika virus (ZIKV). NAAA hydrolyzes the bioactive lipid palmitoylethanolamide (PEA), by lowering lipid availability and counteracting ZIKV replication and virus-associated inflammatory damage. Building on these previous studies, in this work, we explored NAAA therapeutic potential against WNV. Using a next-generation NAAA inhibitor, ARN19702, we demonstrated a marked reduction in WNV replication both in vitro and in vivo. Lipidomic profiling revealed that treatment restored sphingolipid levels, which are otherwise elevated during WNV infection. Moreover, in Golden Syrian hamster models, NAAA inhibition decreased viremia and provided significant protection to the central nervous system, reducing inflammation and virus-induced damage. Together, these findings highlight NAAA inhibition as a promising host-directed therapeutic strategy against WNV and potentially other flavivirus infections.