Linking protein misfolding and heat stress: a common role for the kynurenine pathway

The kynurenine pathway (KP) of tryptophan metabolism is emerging as a key regulator of immune response, neuroinflammation, and neurodegeneration. Tryptophan-derived metabolites influence multiple processes, including excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation, which are underlying mechanisms in major neurological disorders. Dysregulation of the KP leads to an imbalance between neuroactive metabolites such as kynurenic acid quinolinic acid and 3-hydroxykynurenine, contributing to neuronal dysfunction and disease progression. This imbalance is associated with chronic proteinopathies such as Alzheimer's disease and Parkinson's disease, where persistent neuroinflammation and excitotoxicity sustain the activation of KP and subsequent neurodegeneration. Importantly, KP activation is not only limited to chronic conditions but may also occur in acute neurological insults such as heatstroke, where impaired thermoregulation contributes to systemic inflammatory responses, oxidative stress, and disruption of the blood-brain barrier. Consequently, this facilitates the influx of peripheral kynurenine into the brain and its conversion into neuroactive metabolites, linking peripheral immune activation and neuronal injury. These findings highlight KP as a mechanistic bridge between acute and chronic neuropathological processes. In addition, the KP involvement in NAD⁺ production links immune activation and cellular energy metabolism, subsequently increasing neuronal vulnerability, particularly under stress. Emerging evidence further supports the potential of KP metabolites as diagnostic biomarkers for disease progression and severity, as well as possible therapeutic targets. Targeting key enzymes within the KP may offer novel strategies to reduce neurotoxicity and restore metabolic balance, which subsequently improves clinical outcomes.