Abstract

Macrophage metabolic reprogramming toward the M1 phenotype is a key pathological feature of kidney injury. Recent studies have increasingly highlighted the importance of de novo NAD + synthesis in the development of renal damage. In this study, we found that tacrolimus (TAC) suppressed the activity of indoleamine-2,3-dioxygenase 1 (IDO1), thereby blocking the conversion of tryptophan (Trp) to kynurenine (KYN), impairing de novo NAD + synthesis. NAD + deficiency enhances glycolysis, causes accumulation of medium-to long-chain fatty acids and acylcarnitines, indicating impaired fatty acid β-oxidation, thereby promoting M1 polarization and exacerbating renal injury. Further investigations revealed that restoring NAD + levels via exogenous KYN supplementation or directly activating peroxisome proliferator-activated receptor alpha (PPARα) to enhance fatty acid oxidation effectively reversed this metabolic imbalance and alleviated TAC-induced kidney injury.