<b>N-acetyl-tryptophan in acute kidney injury after cardiac surgery</b>

<b>Abstract</b><b>Background</b>: Cardiac surgery-associated acute kidney injury is a common serious complication after cardiac surgery. Currently, there are no specific pharmacological therapies. Our understanding of its pathophysiology remains preliminary.<b>Methods: </b>A total of<b> </b>2504 patients with and without acute kidney injury (AKI) following cardiac surgery were enrolled. High-performance liquid chromatography coupled with mass spectrometry was used for untargeted analysis of metabolites in plasma, identifying significant differential metabolites. Subsequently, a tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was performed for targeted analysis of the metabolic marker N-acetyl-tryptophan. The function of N-acetyl-tryptophan was determined using different renal injury mouse models and epithelial cellular models. The transcriptome sequencing, surface plasmon resonance and protein mutation were employed to explore the mechanism of N-acetyl-tryptophan on the kidney.<b>Results: </b>We identified a total of 32 differential metabolites related to AKI occurrence based on a cohort of 1042 patients. Among them, N-acetyl-tryptophan was elevated in plasma of cardiac surgery-associated acute kidney injury patients compared with those who do not develop AKI after cardiac surgery. The increased level of N-acetyl-tryptophan in plasma was confirmed by accurate targeted quantification. N-acetyl-tryptophan exhibited renal protective effects in I/R-, cisplatin-, and UUO-induced renal injury mouse models. Mechanistically, N-acetyl-tryptophan exerted renal protective effects by interacting with KEAP1 at 483 and 508 sites, resulting in Nrf2 nuclear translocation and the transcription of proteasome genes.<b>Conclusion:</b> N-acetyl-tryptophan plays a key role in kidney protection and provides a potential therapeutic strategy for the treatment of cardiac surgery-associated acute kidney injury.