Lactylation in Sepsis-Associated Acute Kidney Injury: Regulatory Mechanisms and Therapeutic Prospects
This review synthesizes evidence on lactate and lysine lactylation mechanisms in sepsis-associated acute kidney injury, highlighting distinct roles in pathogenesis.
Sepsis-associated acute kidney injury (SA-AKI) represents a prevalent complication of sepsis characterized by high mortality rates and prolonged dependence on organ support. Current therapeutic options remain scarce, necessitating a deeper understanding of underlying metabolic pathways. Beyond serving as an anaerobic glycolysis byproduct, lactate functions as a critical circulating carbon source, mitochondrial fuel, redox regulator, signaling molecule, and substrate for lysine lactylation (Kla). These multifaceted roles are integral to SA-AKI pathogenesis, which involves systemic lactate overload, impaired lactate clearance, renal metabolic reprogramming, and abnormal immune activation.
This review systematically elucidates lactate and Kla mechanisms within the context of SA-AKI. The authors hierarchically integrate findings from systemic sepsis metabolism and renal tubular lactate handling to cell-specific Kla modifications. This approach aims to clarify the distinct roles these molecules play in disease progression, distinguishing between general metabolic states and specific cellular responses.
Specific Kla sites identified include H3K18la, Fis1 K20la, LDHB K156la, Ezrin K263la, HMGB1 lactylation, and ALDH2 K68la. These modifications mediate SA-AKI pathologies such as mitochondrial dysfunction, tubular death, endothelial injury, and cGAS-STING/NLRP3-neutrophil extracellular trap activation. The study emphasizes that 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.
Lactate- and Kla-targeted strategies show promise for SA-AKI treatment but require rigorous clinical validation before widespread application. Blood lactate level and clearance are established as reliable clinical prognostic biomarkers, whereas Kla signatures remain investigational tools. A balanced understanding of lactate-Kla biology is essential to refine precision diagnostic and therapeutic strategies for SA-AKI. This knowledge will advance translational clinical application while maintaining appropriate research-use framing.