Nuclear and Extracellular Lipid Droplets as Novel Players in Viral Infection and Broad-Spectrum Antiviral Strategies

Lipid droplets (LDs) are universal storage organelles for neutral lipids found in most eukaryotic cells. Though their primary function may appear straightforward, LDs are gaining recognition as dynamic organelles that interact with cellular metabolism, signaling, and immunity. The seemingly innocent vesicles are subverted by many viruses, including members of the Flaviviridae family (Hepatitis C virus, Dengue, Zika), to support their replication cycles. Flaviviridae members have been shown to use cytoplasmic lipid droplets (cLDs) as multifunctional platforms, serving as assembly sites, trafficking hubs for viral proteins, and energy stores to fuel replication. While much research has focused on cLDs in the context of viral infection, there is a growing speculation about the potential roles of nuclear LDs (nLDs) and extracellular LDs (eLDs). The normal function of these non-cytoplasmic LD pools remains largely uncharacterized, but they are postulated to serve as scaffolding platforms for proteins and, in the case of nLDs, possible regulators of nuclear processes. This emphasizes the need for further investigation into host LD metabolism. nLDs and eLDs may represent promising targets for host-directed therapeutic strategies against viruses like Dengue and Zika, which currently have no treatment options available. As nLDs and eLDs are an emerging field of study, this article will investigate the normal function of nLDs and eLDs and explore how their cellular processes may be subverted during viral infection. Further, investigating how nLDs and eLDs may influence the design of current inhibitors targeting host lipid metabolism is warranted, as many of these inhibitors have insufficiently understood mechanisms. By shedding light on these understudied aspects of LD biology, this work aims to uncover novel antiviral strategies and deepen our understanding of the complex interplay between viruses and host lipid metabolism.