Lactylation-mitochondria axis in chronic kidney disease: metabolic reprogramming, epigenetic dysregulation, and therapeutic potential.

Chronic kidney disease (CKD) is a global public health problem, and its prevalence and mortality are rising rapidly worldwide. At present, CKD treatment can only partially delay the progression of the disease, and it is necessary to explore safer and more effective treatment options. Renal interstitial fibrosis is a common pathological process in CKD. The essence of renal fibrosis is the excessive deposition of extracellular matrix (ECM), tubulointerstitial fibrosis and glomerulosclerosis caused by various injury reactions, which eventually leads to renal parenchymal destruction and loss of renal function. Therefore, anti-renal fibrosis therapy plays a crucial role in delaying the progression of CKD. Unfortunately, the current treatment options to reverse or prevent the progression of renal fibrosis are very limited. Under normal circumstances, proximal renal tubular epithelial cells mainly rely on fatty acid oxidation (FAO) to obtain energy. In renal tubulointerstitial fibrosis, lipid metabolism disorders occur, resulting in a large amount of lipid deposition in the kidney, causing kidney damage. It can be seen that maintaining the level of FAO metabolism is of great significance for maintaining normal renal function.Kidney is one of the key organs of lactic acid metabolism. Under normal circumstances, renal cortex is the main place of lactic acid metabolism and absorption. In the renal cortex, tubular epithelial cells are the main bearers. This process occurs primarily in the glucose-lactate circulation between the cortex and medulla of the kidney, but the ability of tubular epithelial cells to metabolize lactate is impaired under pathological conditions, especially in acute kidney injury and diabetic nephropathy, resulting in lactic acid accumulation and inflammation and mitochondrial dysfunction. Lactic acid accumulation creates new post-translational modifications-lactylation modifications, metabolic reprogramming resulting from lactylation modifications, regulation of gene transcription, protein expression, and cellular metabolism, critical in renal pathology, and lactylation plays a role in inflammatory responses such as mitochondrial dysfunction in AKD. Intervening in the lactase process in kidney disease may lead to new therapeutic strategies.