SARS-CoV-2 continues to evolve into immune-evasive variants, and although vaccination remains the cornerstone of prevention, the search for antiviral molecules targeting conserved viral enzymes remains essential. The RNA-dependent RNA polymerase (NSP12) is a central component of coronavirus replication, and natural polyphenols have been recurrently proposed as modulators of viral polymerases. Among these compounds, Fisetin has been reported to interact with multiple viral and cellular pathways, yet its direct antiviral activity against SARS-CoV-2 remained largely unexplored. Here, we first analyzed the interaction of Fisetin with the catalytic and NiRAN domains of NSP12 using molecular docking and molecular dynamics simulations, revealing stable and energetically favorable binding throughout a 100 ns simulation. Previous biochemical reports have shown that Fisetin inhibits the recombinant SARS-CoV-2 RdRp, supporting its potential to engage the polymerase. We then evaluated its antiviral activity in human A549 lung epithelial cells infected with the Omicron JN.1 variant. We observed a clear dose-dependent reduction in viral infection, achieving up to 91.9% inhibition at 3 μM while maintaining acceptable cell viability. In addition, Fisetin displayed a selectivity index superior to that of Lopinavir, the positive antiviral control used in this study. Altogether, our findings demonstrate that Fisetin possesses reproducible antiviral activity in a physiologically relevant human lung model and support its role as a natural scaffold for the rational development of polymerase-targeting antivirals against emerging SARS-CoV-2 variants.

RNA virus infections are shaped by the interplay among viral replication, innate immune sensing, and host metabolism, which together determine the magnitude, duration, and quality of antiviral responses. The tryptophan–kynurenine (Trp–Kyn) pathway has emerged as an important immunometabolic axis linking interferon-driven inflammation, amino acid availability, immune-cell function, tissue homeostasis, and viral persistence. This review examines the roles of indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, tryptophan 2,3-dioxygenase (TDO), Trp depletion, general control nonderepressible 2 (GCN2) signaling, mechanistic target of rapamycin complex 1 (mTORC1), Kyn-derived metabolites, and aryl hydrocarbon receptor (AhR) activation in host responses to RNA virus infection. We integrate genetic, pharmacological, cellular, animal, and clinical evidence across positive-sense and negative-sense single-stranded RNA viruses, double-stranded RNA viruses, and reverse-transcribing RNA viruses, including SARS-CoV-2, dengue virus, Zika virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, rotavirus, reovirus, HIV-1, and SIV. Across these systems, the Trp–Kyn–AhR axis can influence interferon responses, viral replication, immune-cell function, tissue injury, and disease outcome. EMCV myocarditis provides causal proof of principle, whereas other RNA-virus models provide complementary functional and clinical evidence. Importantly, pathway activation does not confer a uniform antiviral or pathogenic phenotype; its biological consequences depend on viral class, tissue tropism, viral burden, inflammatory intensity, cell type, and disease stage. On this basis, we propose a time-phase model in which early or excessive IDO1–Kyn–AhR signaling may impair type I interferon responses, NK-cell function, CD8+ T-cell expansion, and viral clearance, whereas appropriately regulated activation during later inflammatory or resolution phases may limit immunopathology, support epithelial repair, and preserve tissue homeostasis. Persistent or dysregulated activation may instead contribute to exhaustion-like immune states, chronic inflammation, neuroimmune dysfunction, and post-acute viral sequelae. Finally, we discuss phase-adapted therapeutic strategies, including IDO1 inhibition, AhR agonism or antagonism, KMO-directed modulation, Trp-based entry inhibitors, and biomarker-guided combination approaches. Together, these findings position the Trp–Kyn–AhR axis as a dynamic, context-dependent target for precision host-directed antiviral immunometabolism.