Targeting the NAD + -SIRT3 axis to mitigate metabolic memory in diabetic kidney disease

Metabolic memory—the persistent risk of diabetic complications after early hyperglycemia—drives progressive renal injury in diabetic kidney disease (DKD) via sustained oxidative stress, inflammation, and epigenetic reprogramming. We synthesize clinical and experimental evidence showing the nicotinamide adenine dinucleotide (NAD+)–SIRT3 (sirtuin 3) axis as a central mechanistic hub linking mitochondrial dysfunction to epigenetic and inflammatory programs in DKD metabolic memory, while evaluating restoration strategies. Integrating data from preclinical, cellular, and human studies, we review SIRT3 biology, compartment-specific renal effects (proximal tubule, podocyte, endothelium), downstream targets, and NAD+/SIRT3-modulating interventions. Key findings show consistently reduced renal SIRT3 expression and activity, driving mitochondrial hyperacetylation, impaired fatty-acid oxidation, persistent ROS, NLRP3/NF-κB–mediated inflammation, and profibrotic signaling. Preclinical NAD+ restoration or SIRT3 activation (e.g., NMN, NR, honokiol, metformin, SGLT2 inhibitors) ameliorates mitochondrial dysfunction, oxidative stress, fibrosis, and albuminuria; however, clinical evidence regarding renal endpoints and SIRT3 engagement biomarkers remains scarce. Translationally, selective kidney-targeted SIRT3 activators, integration with renoprotective therapies, and validated SIRT3 activity biomarkers are priorities to determine if targeting the NAD+–SIRT3 axis can mitigate metabolic memory and slow DKD progression.