Kynurenine Pathway, Nrf2 and NF-κB Cross-Regulation in the CNS: An Overview

Neurodegeneration is characterized by disruptions in metabolic signaling that drive neurons into dysfunctional states, compromising cellular integrity and ultimately leading to cell death. Tryptophan (TRP) metabolism through the kynurenine pathway (KP) plays a central role in neurotransmission, redox balance, and energy metabolism. Alterations in this pathway have been implicated in numerous neurodegenerative conditions. Redox homeostasis is largely governed by the Keap1/Nrf2/ARE pathway, which coordinates the transcription of antioxidant and detoxification responses; however, disruption of this axis exacerbates oxidative stress and neuroinflammation. In turn, the IκBα/NF-κB/IRE pathway controls immune-driven inflammatory states. Crosstalk between these pathways maintains the integrity of metabolic signaling, supporting the adequate functioning of the CNS. In this review, we examine evidence demonstrating that these pathways engage in tight bidirectional communication, with each influencing the other, thereby offering new avenues for investigation in this field. In addition, we conducted bioinformatic analyses to identify potential antioxidant response elements (AREs) and inflammatory response elements (IREs) within the promoter regions of several KP genes, where multiple heterodimers may bind and modulate transcription. Together, the evidence reviewed and our bioinformatic findings support the concept that these pathways engage in reciprocal crosstalk, forming a coordinated signaling axis that preserves CNS homeostasis and helps prevent neurodegeneration.