The metabolic‐immune hub: Dual roles of indoleamine 2,3‐dioxygenase in the acute kidney injury‐to‐chronic kidney disease transition and therapeutic perspectives

Abstract

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a critical determinant of long‐term prognosis, yet the underlying immunometabolic mechanisms remain incompletely defined. Indoleamine 2,3‐dioxygenase (IDO), the rate‐limiting enzyme of the kynurenine pathway (KP) of tryptophan (Trp) metabolism, has emerged as a pivotal metabolic‐immune checkpoint linking cellular metabolism to the immune microenvironment. This review systematically delineates the dual, time‐dependent roles of IDO across the AKI‐to‐CKD continuum. During early AKI, IDO induction confers protection through expansion of regulatory T cells, M2 macrophage polarisation and IDO2‐mediated suppression of ferroptosis via glutathione peroxidase 4 stabilisation. However, sustained IDO activation drives a pathogenic phenotype: persistent Trp depletion activates general control non‐derepressible 2 kinase and the DNA damage response, toxic metabolites, including quinolinic acid (QA), promote tubular dysfunction and fibrosis, nicotinamide adenine dinucleotide (NAD ⁺ ) supply contracts, and sustained aryl hydrocarbon receptor (AhR) signalling reshapes the immune microenvironment towards fibrosis. Concurrently, IDO impairs peritubular capillary stability, and hypoxia‐inducible factor (HIF)–AhR crosstalk via their shared aryl hydrocarbon receptor nuclear translocator (ARNT/HIF‐1β) dimerisation partner amplifies pro‐fibrotic transcription. We synthesise the mechanisms driving this functional reversal, evaluate the kynurenine‐to‐tryptophan ratio as a candidate biomarker for AKI‐to‐CKD risk stratification benchmarked against conventional renal biomarkers, and propose a precision‐timed intervention toolkit, including selective IDO1 inhibitors, AhR modulators, NAD ⁺ precursors, QA scavengers, and senolytic combinations—informed by clinical trial experience from oncology. Gene knockout studies that establish causal roles of IDO and downstream targets are systematically reviewed. The framework reframes IDO as a stage‐specific metabolic‐immune switch whose targeted modulation offers a tractable route to prevent renal fibrosis after AKI.