Molecular mechanisms and targeted intervention strategies of renal tubular epithelial cell glycolytic reprogramming in renal fibrosis.

Renal fibrosis is the core process in the progression of chronic kidney disease (CKD), and its irreversibility leads to end-stage renal disease. Recent studies have shown that metabolic reprogramming, particularly glycolytic reprogramming in renal tubular epithelial cells, is a key mechanism fuels fibrosis, presenting a significant metabolic paradox: short-term adaptive compensation (e.g., enhanced glycolysis) transforms into long-term pathological damage. This review systematically elaborates on the molecular mechanisms of glycolytic reprogramming: 1. FOXK1 forms transcriptional condensates through liquid-liquid phase separation (LLPS) to activate the expression of glycolytic genes, with genetic disruption attenuating fibrosis progression by 48 % (p < 0.01); 2. Pyruvate carboxylase (PC) deficiency triggers a vicious cycle of mitochondrial damage and glycolytic shift, evidenced by a 50 % reduction in PC expression in human fibrotic kidneys (p < 0.001) and a 70 % decrease in basal oxygen consumption rate in PC-knockout models; 3. Epigenetic regulation by metabolic enzymes (e.g., lactylation modification and PKM2 nuclear translocation) forms positive feedback pathways. Based on the above mechanisms, targeted intervention strategies are proposed: inhibiting glycolytic rate-limiting enzymes (HK2, LDHA), repairing mitochondrial function (antioxidation/kinetic regulation), and developing gene/nanotechnology (CRISPR editing, mitochondria-targeted carriers). Finally, current challenges are pointed out, including the spatiotemporal dynamic analysis of LLPS, bottlenecks in kidney-targeted delivery, and the potential of combined immunometabolic therapy, providing a theoretical basis for the development of new anti-fibrotic drugs.