Preclinical experimental study (model species not stated in abstract) · PMID 41929248
Indoleamine 2,3-dioxygenase-regulated macrophages metabolic reprogramming rescues tacrolimus-induced nephrotoxicity
Preclinical study linking tacrolimus kidney toxicity to impaired de novo NAD+ synthesis and M1 macrophage polarization, reversed by restoring NAD+.
Last updated · 2026 · Ye, Zhang, Guo, Zhou, et al. · Frontiers in Pharmacology
Key findings
- Tacrolimus suppressed IDO1 activity, blocking tryptophan-to-kynurenine conversion and impairing de novo NAD+ synthesis
- NAD+ deficiency enhanced glycolysis and caused accumulation of medium- to long-chain fatty acids and acylcarnitines, indicating impaired fatty acid beta-oxidation
- This metabolic shift promoted M1 macrophage polarization and worsened renal injury
- Restoring NAD+ with exogenous kynurenine, or activating PPARalpha, reversed the imbalance and alleviated tacrolimus-induced kidney injury
Study Design
- Preclinical laboratory study of tacrolimus (TAC)-induced kidney injury; the abstract does not specify the animal model or cell systems used
- Measured IDO1 activity, tryptophan (Trp) to kynurenine (KYN) conversion, NAD+ synthesis, glycolysis, fatty acids/acylcarnitines, and macrophage polarization
- Rescue arms: exogenous KYN supplementation and direct PPARalpha activation
Key Results
- TAC —> suppressed IDO1 activity —> blocked Trp-to-KYN conversion —> impaired de novo NAD+ synthesis
- NAD+ deficiency —> enhanced glycolysis + accumulation of medium- to long-chain fatty acids and acylcarnitines (impaired beta-oxidation)
- Metabolic shift —> M1 macrophage polarization —> worsened renal injury
- Rescue: restoring NAD+ via exogenous KYN, or activating PPARalpha to enhance fatty acid oxidation, reversed the imbalance and alleviated kidney injury
Mechanism Insight
Links a drug-induced drop in de novo NAD+ synthesis (the tryptophan-kynurenine pathway) to macrophage metabolic reprogramming toward the pro-inflammatory M1 phenotype, a feature the authors describe as key in kidney injury.
Clinical Relevance
Preclinical only. The study did not test NAD+ precursors or any treatment in patients; the rescue strategies were exogenous KYN and PPARalpha activation. Whether these findings apply to transplant recipients taking tacrolimus has not been tested.
See Also
- Parent compound: NAD+
Where to buy NAD+
NAD+10 vetted vendors
BioLongevity LabsVisit BioLongevity Labs →
Save 15% with code VIALBASE
VialBase may earn a commission on partner links — never at extra cost to you. Disclosure.