Lactylation at the crossroads of metabolism and immunity in renal injury and transplant rejection.
TL;DR
Understanding the role of lactylation and lactic acid-induced immune cell malfunction in renal pathophysiology provides not only mechanistic insight but also potential therapeutic targets for acute kidney injury, chronic kidney disease, and transplant rejection.
Abstract
Lactate, once regarded merely as a metabolic waste product of glycolysis, has recently emerged as a potent signaling molecule and regulator of cellular function. The discovery of protein lactylation, a novel post-translational modification derived from lactate metabolism, has revealed a critical mechanism linking metabolic activity with epigenetic and functional reprogramming of cells. Both histone and non-histone lactylation serve as integrators of glycolytic flux, modulating gene expression, enzyme activity, and immune responses in diverse physiological and pathological contexts. The immune system is particularly sensitive to these metabolic cues. Accumulation of lactate in hypoxic or inflamed tissues reprograms macrophages, neutrophils, NK cells, and T cells through lactylation, shaping their activation, polarization, and effector functions. In the kidney, which is highly vulnerable to hypoxia and metabolic stress, lactate-driven immune reprogramming has profound consequences. Acute insults such as ischemia-reperfusion injury (IRI) and acute rejection (AR) in transplantation are characterized by glycolytic metabolic reprogramming and lactate accumulation, which in turn influence immune and parenchymal cell behavior. Thus, understanding the role of lactylation and lactic acid-induced immune cell malfunction in renal pathophysiology provides not only mechanistic insight but also potential therapeutic targets for acute kidney injury, chronic kidney disease, and transplant rejection.