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

Type I interferons exhibit potent broad-spectrum antiviral activity in preclinical studies but suffer from critical clinical limitations: narrow intervention windows for acute infections, suboptimal efficacy, and notable adverse reactions. 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. Based on this mechanism, we developed a combinatorial therapy of IFNs plus an FDA-approved lactate dehydrogenase inhibitor. This regimen reverses LAC-mediated IFN suppression, mitigates inflammation, and achieves dual "antiviral + anti-inflammatory" benefits. Notably, it retains robust efficacy even in late-stage infections, overcoming IFN monotherapy drawbacks and addressing the core bottleneck restricting IFN clinical application. Our study identifies LAC as a pivotal target for broad-spectrum antiviral development and provides a potential strategy to combat emerging viral pandemics.