Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production.

Summary

Amlexanox improved survival and organ function in endotoxemia and sepsis by elevating intracellular lactate, which increased histone lactylation at the IL10 promoter and boosted IL-10 production. Blocking IL-10 signaling or inhibiting lactate production abrogated benefits, and sodium lactate alone improved survival, positioning lactate-mediated epigenetic reprogramming as protective in sepsis.

Key Findings

• Amlexanox increased intracellular lactate, enhanced histone lactylation at the IL10 promoter, and elevated IL-10, improving survival and reducing organ injury in endotoxemia and sepsis models.
• Blocking IL-10 receptor signaling or inhibiting lactate production abrogated amlexanox’s therapeutic effect, establishing causality.
• Amlexanox suppressed electron transport chain gene expression, decreased OCR, and increased ECAR, indicating metabolic reprogramming toward lactate production; in vivo sodium lactate also improved survival.

Clinical Implications

Suggests testing amlexanox and controlled lactate elevation strategies to modulate IL-10 in early-phase clinical trials, with biomarkers such as histone lactylation to guide dosing and response.

Limitations

• Preclinical models (endotoxemia and sepsis) may not fully recapitulate human heterogeneity.
• Safety, dosing, and timing of lactate elevation/amlexanox require clinical evaluation.

Future Directions

Prospective early-phase trials of amlexanox with pharmacodynamic monitoring of histone lactylation and IL-10; exploration of patient subsets most likely to benefit.