The lactate-lactylation axis in acute kidney injury: mechanisms from metabolic reprogramming to epigenetic regulation and clinical therapeutic prospects.

Acute kidney injury (AKI) is a common critical clinical syndrome among hospitalized patients, characterized by high incidence and mortality rates. Currently, the pathogenesis of AKI remains incompletely understood, and effective clinical treatments are lacking. Lactate, a metabolic byproduct of glycolysis, is involved in numerous pathophysiological processes within the kidney and functions as a regulator of lactylation, a recently identified posttranslational modification (PTM). The regulation of lactylation is closely controlled by several key enzymes and metabolic pathways, creating a dynamic and complex modification network. By modulating protein function and gene expression, lactylation significantly impacts the progression of various diseases. Recent evidence suggests that lactylation acts as a pivotal regulatory hub in the pathophysiology of AKI and is intricately linked to core AKI mechanisms, such as inflammation, metabolic reprogramming, and mitochondrial dysfunction. This review presents an investigation of renal lactate metabolism homeostasis and the disruption of this homeostasis, thoroughly discussing the biological underpinnings of lactylation, including the core enzymes involved, and focuses on elucidating the mechanisms of lactylation in AKI. Additionally, the potential of targeting the lactate-lactylation axis as a promising therapeutic strategy for AKI is discussed.