Beyond Viral Restriction: The Metabolic Dimensions of Interferon-Stimulated Genes in Antiviral Immunity

Interferon-stimulated genes (ISGs) are classically recognized for their direct antiviral functions, such as viral genome degradation or replication blockade. However, emerging evidence reveals that ISGs orchestrate a broader landscape of host defense by rewiring cellular metabolism. These mechanisms are still not fully understood in the context of antiviral immunity. This review synthesizes recent advances in understanding how ISGs modulate metabolic pathways (e.g., glycolysis, lipid metabolism, amino acids, and nucleotide metabolism) to create an antiviral cellular environment. However, viruses have developed strategies to evade or counteract ISG-encoded proteins, and some even hijack certain ISGs to their advantage. Therefore, we further explore how viruses subvert these ISG-driven metabolic to evade host defenses. Overall, we summarize the current state of knowledge on the interactions between viruses and ISGs and propose that ISGs act as "protective" or "pathogenic" regulators at the dimensions of metabolism, offering new perspectives for targeting host-centered pathways to combat viral infections.