Lactylation in sepsis-associated acute kidney injury: regulatory mechanisms and therapeutic prospects.

INTRODUCTION

Sepsis-associated acute kidney injury (SA-AKI) is a prevalent, life-threatening sepsis complication with high mortality, prolonged organ support dependence, and scarce targeted therapies. Beyond being an anaerobic glycolysis byproduct, lactate serves as a critical circulating carbon source, mitochondrial fuel, redox regulator, signaling molecule, and lysine lactylation (Kla) substrate. Its multifaceted functions are vital to SA-AKI pathogenesis, which involves systemic lactate overload, impaired lactate clearance, renal metabolic reprogramming, and abnormal immune activation.

METHODS

This review synthesizes up-to-date evidence to systematically elucidate lactate and Kla mechanisms in SA-AKI. We hierarchically integrate findings from systemic sepsis metabolism and renal tubular lactate handling to cell-specific Kla modifications, aiming to clarify their distinct roles in SA-AKI progression.

RESULTS

Specific Kla sites (H3K18la, Fis1 K20la, LDHB K156la, Ezrin K263la, HMGB1 lactylation, ALDH2 K68la) mediate SA-AKI pathologies including mitochondrial dysfunction, tubular death, endothelial injury, and cGAS-STING/NLRP3-neutrophil extracellular trap activation. Lactate accumulation, acidosis, transport, oxidation, metabolic routing, and Kla are mechanistically distinct rather than uniformly harmful. Lactate/pyruvate metabolism exerts context-dependent injurious or adaptive effects across kidney disease models, modulated by cell type, injury phase, and metabolic reserve.

DISCUSSION: Lactate- and Kla-targeted strategies are promising for SA-AKI treatment yet require rigorous clinical validation. Blood lactate level and clearance are reliable clinical prognostic biomarkers, whereas Kla signatures remain investigational. Balanced understanding of lactate-Kla biology will refine precision diagnostic and therapeutic strategies for SA-AKI, advancing translational clinical application.