The multifaceted roles of nucleolin in viral entry, replication, and antiviral therapy.

Nucleolin (NCL) is a multifunctional, highly conserved protein that shuttles between the nucleus, cytoplasm, and cell surface, playing pivotal roles in cellular homeostasis and disease. In recent years, NCL has emerged as a central host factor exploited by a wide array of viruses-including Herpesviridae, Flaviviridae, Pneumoviridae, Picornaviridae, Orthomyxoviridae, Coronaviridae, Caliciviridae, and Morbillivirus-to facilitate viral entry, replication, assembly, and immune evasion. This review provides a comprehensive, comparative synthesis of the mechanisms by which diverse viruses hijack distinct structural domains of nucleolin, highlighting both proviral and antiviral activities that are context- and compartment-dependent. We critically evaluated the strength and limitations of current evidence, discuss contradictory findings across virus families, and identify patterns in domain-specific and compartmentalized viral exploitation of NCL. Special emphasis is placed on recent advances in targeting nucleolin-virus interactions for therapeutic intervention, including aptamers, G-quadruplex stabilizers, and domain-specific inhibitors. While nucleolin's essential cellular functions present challenges for drug development, emerging strategies that exploit its unique roles in viral pathogenesis offer promising avenues for broad-spectrum and precision antivirals. By integrating mechanistic insights across virus families, this review positions nucleolin as a universal node in viral infection and a compelling target for next-generation antiviral therapies.