Adipose Mesenchymal Stem Cells Secreted Exosomal miR-26a-5p Ameliorate Renal Fibrosis via Inhibiting Glycolysis and Ferroptosis in Renal Interstitial Fibrosis.

Renal fibrosis, a defining feature of chronic kidney disease, involves a metabolic shift toward aerobic glycolysis and is frequently accompanied by ferroptosis, a form of iron-dependent cell death. This study investigated the therapeutic potential of adipose mesenchymal stem cell-derived exosomes (AMSC-exo) in renal fibrosis. Using a unilateral ureteral obstruction (UUO) mouse model and hypoxia-treated HK-2 cells, we assessed fibrosis, glycolysis, mitochondrial morphology, and ferroptosis. miRNA sequencing, dual-luciferase reporter assays, and transcriptome sequencing were performed to identify key exosomal miRNAs and downstream pathways. AMSC-exo significantly attenuated UUO-induced fibrosis and suppressed glycolysis and ferroptosis in tubular epithelial cells. miR-26a-5p was highly enriched in AMSC-exo and downregulated 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a key regulator of glycolysis and ferroptosis. Knockdown of miR-26a-5p markedly weakened the renoprotective effects of AMSC-exo, whereas Pfkfb3 inhibition reversed the effects induced by miR-26a-5p deficiency. These findings indicate that AMSC-exo alleviate renal fibrosis by delivering miR-26a-5p to suppress Pfkfb3, thereby inhibiting glycolytic reprogramming and ferroptosis, and suggest the miR-26a-5p/Pfkfb3 axis as a potential therapeutic target for renal fibrosis.