MiR-30d-5p Modulates Glucose and Lipid Metabolism by Targeting CD73 through the AMPK Pathway.

Abstract

Type 2 diabetes (T2D) involves disrupted metabolism and immune responses, but mechanisms remain unclear. This study examines CD73 and its potential regulation by miR-30d-5p via the AMPK pathway. In db/db mice and clinical T2D patients, we observed significantly elevated hepatic CD73 expression inversely correlated with miR-30d-5p levels. siRNA-mediated CD73 silencing disrupted glucose-lipid metabolic stability by enhancing AMPK phosphorylation, suggesting CD73's regulatory role in energy homeostasis. Bioinformatics analysis identified CD73 as a putative target of miR-30 family members, which was experimentally validated through dual-luciferase reporter assays demonstrating miR-30d-5p's direct binding to two conserved sites within CD73's 3'-UTR. Notably, miR-30d-5p overexpression mimicked CD73 knockdown effects, downregulating key gluconeogenic enzymes while upregulating lipid oxidation markers. The inverse expression patterns of CD73 and miR-30d-5p in both murine models and human peripheral blood samples underscore their antagonistic relationship in T2D progression. These findings position the miR-30d-5p/CD73 axis as a critical regulator of hepatic AMPK-mediated metabolic processes, offering novel therapeutic targets. Our work bridges the gap between immune-modulatory pathways and metabolic regulation, proposing CD73 inhibition as a dual-action strategy for improving insulin sensitivity and mitigating diabetic complications. This mechanistic insight advances precision medicine approaches for T2D management by integrating epigenetic regulation with enzymatic metabolic control.