Host-derived lactic acid disrupts IFN efficacy via antiviral inhibition and proinflammatory amplification

Circulating emerging viruses endanger public health. Type I interferons (IFNs) confer robust preclinical antiviral efficacy yet face incompletely defined clinical hurdles: narrow therapeutic windows, suboptimal activity and severe adverse events. Herein, we show that IFNs confer antiviral protection exclusively upon pre-infection administration. 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 Silent Information Regulator 1 (SIRT1) upregulation and synergizes with IFNs to hyperactivate Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NF-κB), initiating cytokine storms and forming an "antiviral failure-inflammatory amplification" feedback loop. Based on this mechanism, we develop a combinatorial therapy of IFNs plus an U.S. Food and Drug Administration (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.