Targeting Lactic Acid Unleashes IFN’s Potent Broad-Spectrum Antiviral Efficacy and Overcomes Clinical Limitations.

The discrepancy between their robust preclinical and limited clinical performance remains mechanistically unclear. Herein, integrating clinical samples and multi-level infection models, we demonstrate that IFNs exert antiviral effects only when administered pre-infection.

Once infection is established, IFNs are ineffective yet induce prominent adverse effects, with host-derived lactic acid (LAC) as the key mediator: it promotes viral immune evasion, impairs IFN therapeutic efficacy, triggers inflammatory storms, and elicits adverse reactions. Mechanistically, LAC suppresses IFN activity via membrane receptor-mediated SIRT1 upregulation and synergizes with IFNs to hyperactivate NF-κB, initiating cytokine storms and forming an "antiviral failure-inflammatory amplification" feedback loop.