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

Abstract

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.

Graphical abstract

Introduction

The kynurenine pathway (KP), initiated through the oxidative degradation of tryptophan, has been the subject of investigation since the early twentieth century. Metabolites of tryptophan (TRP) exert diverse biological effects, including the modulation of excitotoxic neurotransmission, oxidative stress, neurotransmitter transport, neuroinflammatory responses, protein aggregation, microtubule dynamics, and gut microbiota homeostasis. Beyond the central nervous system (CNS), the KP also contributes to allergic reactions, immune regulation, mitochondrial function, and cellular bioenergetics through its role in maintaining cellular redox balance. More recently, the KP has emerged as a critical regulator of both central and peripheral immune and inflammatory processes. Its metabolites can suppress the proliferation of intracellular pathogens, promote maternal immune tolerance, and regulate apoptosis, thereby influencing cell cycle progression (Fallarino et al. 2003). Dysregulation of the KP is strongly associated with the development of neurological and neurodegenerative disorders. These shared mechanisms highlight the relevance of KP-related processes not only in chronic neurodegenerative diseases but also in acute syndromes, where rapid neuroinflammation and excitotoxic stress contribute to neuronal damage.

Proteinopathies, characterized by the abnormal aggregation of specific proteins in the brain, underlie the majority of neurodegenerative diseases. This group includes conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). These disorders are typically associated with chronic neuroinflammation, involving activation of resident brain immune cells and infiltration of peripheral immune cells into the CNS (Starhof et al. 2018). Neuroinflammation is characterized by the release of a broad spectrum of cellular and molecular mediators, including pro-inflammatory cytokines, chemokines and complement components which contribute to immune activation. In the CNS, microglia and astrocytes serve as the primary source of pro-inflammatory molecules such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (Liu et al. 2017a, b).

Neuroinflammation is the immune-mediated inflammatory response that occurs following injury or exposure to pathological stimuli. CNS insults rapidly activate immune mechanisms, particularly through the recruitment and activation of resident glial cells. Acute neurological conditions, such as heatstroke, are accompanied by inflammatory responses and disruption of the blood–brain barrier (BBB) (Li et al. 2025). Heatstroke is characterized by a systemic inflammatory response involving elevated pro-inflammatory cytokines, which correlate with disease severity and contribute to multiorgan dysfunction (Li et al. 2023). These processes converge on shared pathological pathways, including mitochondrial dysfunction, inflammatory activation, and impairment of protein degradation systems. Notably, activation of the kynurenine pathway during heat stress further links metabolic and inflammatory responses to excitotoxicity and protein aggregation. Together, these overlapping mechanisms suggest that heatstroke may not only mimic key features of proteinopathies but also contribute to their initiation or progression under certain conditions.

Overall, the study of tryptophan metabolism and the mechanisms by which its metabolites regulate inflammation and neurodegeneration remains a highly promising field. It offers significant potential for the development of novel therapeutic strategies targeting neurodegenerative diseases, cognitive disorders, and acute neurological conditions such as heatstroke.

Literature search

We used PubMed, Web of Science, and Google Scholar to search for targeted literature using a combination of terms related to the kynurenine pathway and tryptophan metabolism, along with terms related to neuroinflammation, proteinopathy, oxidative stress, and heatstroke. Articles were included if they addressed KP metabolism or its relationship to neuronal injury, protein aggregation, and heat-related neurological injury. The search included literature available through 2026. Reference lists of relevant articles were also screened to identify additional studies.

Tryptophan metabolism

The essential amino acid L-tryptophan (TRP) is a precursor to many important biologically active molecules. The human body cannot synthesize TRP, so it must be obtained from the diet. Upon reaching the gastrointestinal tract, TRP can be utilized and metabolized by the gut microbiome. Some gut microorganisms, such as Enterococcus, Escherichia, Candida, and Streptococcus, can express the enzyme tryptophan synthase, which catalyzesthe biosynthesis of TRP from serine and indole-3-glycerol phosphate (Roth et al. 2021).

From a chemical perspective, the structure of TRP is based on an indole (a bicyclic ring composed of pyrrole and benzene), connected to the α-carbon by a single -CH₂ group. The presence of the indole ring is responsible for the hydrophobic properties of TRP. In addition, it contains 11 carbon atoms, the highest among all amino acids.

After absorption, TRP is transformed into a series of small bioactive molecules, all of which influence numerous cellular metabolic pathways and physiological responses (regulation of immune, gut, endocrine, cardiovascular, and neurological functions). Changes in their concentrations are therefore often associated with various diseases and syndromes, including neurodegenerative disorders such as AD and PD (Palego et al. 2016).

In humans, up to 90% of TRP circulates in the blood in a free (unbound) form, while the remaining 10% is bound to albumin (Lovelace et al. 2017). Most TRP undergoes various reactions (such as oxidation, hydroxylation, deamination, decarboxylation, or transamination), and it is catabolized/metabolized via three pathways: the kynurenine pathway (occurring mainly in the liver: 90%, and in the brain and gut: 10%), the serotonin pathway (occurring mainly in the gastrointestinal tract: 90%, and in the nervous system: 10%), and the indole pathway (mediated by gut microbes and occurring in the intestine). An illustration of these three TRP metabolic pathways is shown in Fig. 1. The remaining absorbed TRP is used for protein synthesis (Roth et al. 2021).

Fig. 1.

Metabolic pathways of tryptophan (TRP) degradation. The kynurenine pathway (KP) converts TRP to kynurenine (KYN), which branches into kynurenic acid (KA), anthranilic acid (AA), and 3-hydroxykynurenine (3-OH KYN), ultimately yielding quinolinic acid (QA) and feeding into NAD⁺ biosynthesis. The indole pathway (I) generates tryptamine (TRM), indole-3-pyruvic acid (IPYA), and related intermediates, converging on end products such as indole-3-propionic acid (IPA) and indole-3-acetic acid (I3AA). The serotonin pathway (S) proceeds via 5-hydroxytryptophan (5-OH TRP) to serotonin (5-HT), then to N-acetylserotonin (NAS), melatonin (MEL), and its degradation product AFMK. Structures are shown for all intermediates; the dashed arrow indicates a multi-step conversion. 3-OH AA 3-hydroxyanthranilic acid, 3-OH KYN 3-hydroxykynurenine, 5-HT serotonin, 5-OH IAA 5-hydroxyindole-3-acetic acid, 5-OH TRP 5-hydroxytryptophan, AA anthranilic acid, ACMSA 2-amino-3-carboxymuconate semialdehyde, AFMK N-acetyl-N-formyl-5-methoxykynurenamine, CA cinnabarinic acid, FHKA formyl-5-hydroxykynurenamine, HIAa 5-hydroxyindole-3-acetaldehyde, I3AA indole-3-acetic acid, I3LA indole-3-lactic acid, IA indoleacrylic acid, IAAld indole-3-acetaldehyde, IAM indole-3-acetamide, ICA indole-3-carboxaldehyde, IPA indole-3-propionic acid, IPYA indole-3-pyruvate, KA kynurenic acid, KYN kynurenine, MEL melatonin, MES N-methylserotonin, NA nicotinic acid, NAD⁺ nicotinamide adenine dinucleotide, NAMN nicotinamide mononucleotide, NAS N-acetylserotonin, PA picolinic acid, QA quinolinic acid, TRM tryptamine, TRP tryptophan, XA xanthurenic acid (created using ChemDraw Professional 16.0.1.)

TRP and its metabolites have emerged as potential biomarkers for the diagnosis and monitoring of both chronic neurodegenerative diseases, including AD and PD, and acute neurological syndromes such as heatstroke. In the context of heatstroke, alterations in TRP metabolism may reflect acute neuroinflammation, excitotoxic stress, and blood–brain barrier (BBB) dysfunction, providing insight into the severity of neuronal injury. Alterations in TRP metabolism reflect ongoing neuroinflammatory processes and excitotoxic stress, providing insight into disease severity and progression. Measurement of TRP and its metabolites in blood or CSF may help in early diagnosis and ongoing monitoring of neurodegenerative and neurological diseases.

Kynurenine pathway

The kynurenine pathway (KP) is the dominant catabolic pathway of TRP (Savonije and Weaver 2023). Generally around 90–95% of absorbed TRP enters the KP and is transformed into the unstable N-formylkynurenine via indoleamine 2,3-dioxygenase (IDO1) or tryptophan 2,3-dioxygenase, which is subsequently converted into the aryl hydrocarbon receptor (AhR) ligand-KYN-in a reaction catalyzed by N-formylkynurenine formamidase (Atsumi et al. 2019). N-formylkynurenine is the initial product formed when IDO1 converts TRP, which is subsequently converted to KYN. KYN can then be metabolized either into KYNA via kynurenine aminotransferases or into 3-HK via kynurenine monooxygenase (KMO), although the relative contribution of each pathway differ by cell type. 3-HK is further converted either into XA or into 3-OH AA, which can also be formed directly from KYN through AA. Through a series of enzymatic reactions, additional intermediates such as PA and QA are generated, with the final product of this pathway being NAD⁺, a molecule crucial for energy metabolism.

TRP is actively transported across the blood–brain barrier (BBB) via large neutral amino acid (LNAA) transporters, primarily LAT1 (L-type amino acid transporter 1). During inflammatory conditions, enhanced degradation of TRP through the KP increases the availability of peripheral kynurenine, which can also cross the BBB and enter the CNS. It has been estimated that up to 60% of brain KYN is derived from peripheral sources (Gal and Sherman 1980). Under physiological conditions, LAT-1 transporter is nearly saturated; however, in AD, alterations in the TRP/LAT-1 ratio may influence TRP availability in the brain (Xie et al. 2024).

In addition to KYN, other TRP metabolites, such as KYNA, AA, and 3-OH AA, are endogenous ligands for AhR, which in turn regulates immune cell functions (Hajsl et al. 2020). Intermediates of this pathway represent important molecules often associated not only with neurological disorders (Lovelace et al. 2017) and neurodegenerative diseases, such as, Parkinson´s disease (Zhang et al. 2025) or AD (Liang et al. 2022).

Some metabolites generated in the KP are neuroactive, in part through their effects on N-methyl-D-aspartate (NMDA) receptor signaling. For example, KYNA (an NMDA antagonist) and PA have been widely associated with neuroprotective molecules, whereas QA (an NMDA agonist), 3-OH AA, and 3-HK are neurotoxic (Dehhaghi et al. 2022). Elevated QA levels has been associated with neuropathic pain, suggesting that QA may contribute to neuronal dysfunction in neurological diseases (Maganin et al. 2022). Changes in TRP metabolism have been shown to have various effects on the potential neurotoxicity of Aβ and α-synuclein or tau protein aggregates (Kaleta et al. 2024). Metabolic disturbances in the KP can be reflected by an increased KYN/TRP ratio, which may also indicate a higher risk of CNS disorders, suggesting that this ratio could serve as a useful biomarker (Liang et al. 2022).

Serotonin pathway

A small portion (approximately 5% of TRP) enters the serotonin pathway (SP), where it is first converted into 5‑OH TRP, which is then transformed into the neurotransmitter 5‑HT (serotonin) (Davidson et al. 2022). These reactions are catalyzed by tryptophan hydroxylase and 5‑hydroxytryptophan decarboxylase. Acetylation of 5‑HT catalyzed by arylalkylamine N‑acetyltransferase produces N-acetylserotonin (NAS), which is a precursor of melatonin (MEL, the main endogenous regulator of circadian rhythms).

5‑HT can also be catabolized into FHKA by IDO1, into MES by indolethylamine N‑methyltransferase, or by monoamine oxidase into HIAa, which is subsequently converted by aldehyde dehydrogenase into the major metabolite 5‑OH IAA (Hajsl et al. 2020). 5‑OH IAA is associated with dementia with Lewy bodies (DLB) and AD (Morimoto et al. 2017). It has been shown that 5‑OH IAA, together with homovanillic acid (a dopamine metabolite), may serve as potential biomarkers to distinguish DLB from AD (Morimoto et al. 2017).

Alongside other neurotransmitter systems (cholinergic, dopaminergic), the serotonergic system is also involved in AD progression. In AD, not only is a decrease in 5‑HT receptors observed in various brain regions (cortex and hippocampus) (Lorke et al. 2006; Mizukami et al. 2011), but also a reduction in 5‑HT and 5‑OH IAA levels (Reinikainen et al. 1988). Therefore, therapies based on selective serotonin reuptake inhibitors have proven effective in this pathway.

Indole pathway

This route of TRP degradation is primarily mediated by gut microorganisms, which produce indole-based metabolites through the indole pathway (IP) (Lefevre et al. 2019). Examples of such indole metabolites include IPA, I3AA, and I3LA. These indoles may provide protection against oxidative stress, which is associated with AD. For example, IPA has antioxidant effects and can reduce Aβ aggregation. Not only IPA but also other metabolites such as TRM, I3AA, and I3LA may potentially inhibit Aβ aggregation and slow AD progression. Neuroprotective effects have also been demonstrated for I3AA, which activates AhR in microglia and astrocytes, leading to reduced neuroinflammation in AD. Serum and CSF levels of I3AA were lower in AD patients compared to non-AD individuals. Despite these findings, further research is needed on the impact of IP metabolites on AD progression (Zhou et al. 2023).

TRP and its metabolites have emerged as potential biomarkers for the diagnosis and monitoring of neurodegenerative disease progression, including AD and PD. Alterations in TRP metabolism, particularly along the KP, reflect ongoing neuroinflammatory processes and excitotoxic stress, providing insight into disease severity and progression. Measurement of TRP and its metabolites in blood or CSF may help in early diagnosis and ongoing monitoring of neurodegenerative diseases.

TRP can be distributed among three pathways the KP pathway, the serotonin synthesis pathway, and the microbial indole pathway. However, the relative contribution of these pathways can vary with physiological or pathological conditions, with inflammation particularly altering this distribution, especially in the KP. Inflammatory signals, particularly IFN-γ and other pro-inflammatory cytokines, promote IDO activity, which converts TRP into KYN. This shifts TRP toward the KP. The KP is particularly responsive to inflammatory states, making it a major metabolic route during immune activation and potentially altering TRP availability for serotonin and the microbial indole pathway. The downstream metabolites of the KP, such as KYNA, 3-HK, and QA, have been linked to oxidative stress, neuroinflammation, and excitotoxicity (Guidetti et al. 2004; Pérez-De La Cruz, Carrillo-Mora et al. 2012, Tavassoly et al. 2018). Conversely, TRP utilization in serotonin synthesis isn’t primarily induced by inflammatory cytokines, as in the KP. Therefore, when there is an increased inflammatory response alongside KP activity, TRP may shift toward the KP, leaving less TRP available for serotonin synthesis. Additionally, the microbial indole pathway involves gut microbes using dietary TRP to produce indole derivatives, so an increase in TRP use in the KP reduces the availability of TRP to the microbiota. However, this pathway depends on intestinal conditions and the microbiome, indicating that inflammatory processes do not universally inhibit indole production (Hou, Li et al. 2023; Li 2023).

The neuromodulatory roles of kynurenines

Acute or chronic stress, infections, inflammatory responses, and the accumulation of toxins disrupt homeostasis in the KP, leading to dysregulation of the pathway and altered production of neuroactive metabolites (Leng and Edison 2021). Nevertheless, the factors that determine whether brain kynurenine metabolism shifts toward neuroprotective or excitotoxic metabolites remain poorly understood.

Kynurenine metabolites can exhibit both neuroprotective and neurotoxic effects depending on concentration, disease state, cell type, and the balance between downstream metabolites.

Pro-inflammatory cytokines play a key role in regulating the activity of indoleamine 2,3-dioxygenase 1 (IDO1), thereby activating IDO1 and leading to a subsequent shift in TRP metabolism toward the KP. IDO1 expression is induced by pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α; chemokine ligands such as C-C motif chemokine ligand 1 and 5 (CCL1 and CCL5); and small signaling molecules, including prostaglandins, nitric oxide (NO), and reactive oxygen species (ROS) (DiSabato et al. 2016). The production of ROS, increased TNF-α, and cytokine secretion further promote interferon-gamma (IFN-γ) production, which in turn stimulates IDO1 activity in astrocytes, microglia, and other inflammatory cells (Schwarcz and Stone 2017). Activation of IDO1 results in decreased TRP availability and increased levels of tryptophan catabolites (Maes 2011). The KP generates several neuroactive and potentially neurotoxic metabolites, including QA, XA, 3-HAA, 3-HK, and PA (Fig. 2).

Fig. 2.

Inflammatory modulation of kynurenine pathway metabolism and its relationship to neuronal injury. Inflammatory conditions increase IDO/KP activity and shift the balance of downstream kynurenine metabolites. This altered metabolic balance may contribute to excitotoxicity, oxidative stress, and neuroinflammation, thereby increasing neuronal injury

Pro-Inflammatory cytokines play a broader role beyond IDO activation in contributing to neuronal injury. Evidence further highlights their role in inflammatory signaling, which has been linked to oxidative stress, mitochondrial dysfunction, and disruption of the BBB. In Parkinson’s disease, inflammatory signaling involving NF-κB and the NLRP3 inflammasome has been associated with increased production of pro-inflammatory cytokines, which have been implicated in oxidative stress, disruption of the BBB, and neuronal injury. This provides a complementary mechanism to the cytokine-IDO-KP axis (Alshahrani et al. 2025).

The neuroactive effects of kynurenine metabolites are mediated primarily by two mechanisms: modulation of cellular receptor activity and regulation of redox processes within neurons and glial cells. Kynurenine 3-monooxygenase (KMO) is a key enzyme in the KP and a major determinant of tryptophan metabolism. Nonetheless, KMO inhibition using JM6 reversed spatial memory deficits and anxiety-like behaviors in mice (Zwilling et al. 2011), and in a mouse model of AD, KMO inhibition prevented synapse loss and improved spatial memory.

These findings highlight how alterations in KMO activity shift the balance of downstream kynurenine metabolites, such as KYNA, 3-HK, and QA, toward either neuroprotective or excitotoxic route. Understanding how the KP flux is regulated under physiological and pathological conditions is therefore critical for identifying therapeutic strategies to mitigate excitotoxicity while enhancing neuroprotection.

It is important to note that these metabolites do not function as independent mediators but are interconnected within the same metabolic pathway. Hence, the biological effect depends on the relative balance between the downstream neuroprotective and neurotoxic metabolic properties rather than on changes in the absolute concentrations of individual metabolites in the KP. For instance, in inflammatory responses, KP activity can alter metabolic flux between branches, changing the relative production of its downstream metabolites. This shift may influence mechanisms such as neuroinflammation, oxidative stress, or extracellular toxicity (Fathi et al. 2022).

Kynurenic acid

Within this balance in the KP, KYNA represents a crucial downstream metabolite that can contribute to neuroprotective effects. KYNA acts as an NMDA receptor antagonist and can protect neurons against QA-induced excitotoxicity. In the brain, KYNA is synthesized de novo in astrocytes by KAT II following uptake of kynurenine via the LAT-1 (Kiss et al. 2003).

KYNA exerts diverse neuromodulatory effects, influencing glutamatergic, cholinergic, GABAergic, and dopaminergic neurotransmission (Flores-Barrera and Thomases 2017). At low concentrations, it prevents excitotoxic neuronal damage, although the exact CNS levels required for neuroprotection remain unclear. Dysregulation of kynurenine 3-monooxygenase activity can lead to significantly elevated KYNA levels, as observed in patients with AD compared to controls (Gonzalez-Sanchez et al. 2020).

KYNA also modulates oxidative stress by attenuating activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of cellular antioxidant defense, thereby reducing the impact of ROS, lipid peroxidation, protein damage, and mitochondrial respiratory dysfunction induced by QA (Pierozan and Biasibetti-Brendler 2018).

Although generally considered neuroprotective, excessive accumulation of KYNA above physiological levels can impair glutamatergic signaling and contribute to cognitive decline (Kozak et al. 2014). This is partly due to its antagonistic action on α7-nicotinic acetylcholine receptors (α7nACh-R) and its regulatory effects on other acetylcholine receptor subtypes.

Hydroxykynurenine

In contrast, 3-HK represents a redox–sensitive branch of KP metabolism and links altered KP flux to oxidative stress. 3-hydroxykynurenine, exhibits both antioxidant and pro-oxidant properties depending on its concentration. Lower concentrations are associated with strong pro-oxidant activity and neurotoxicity (Reyes-Ocampo and Lugo-Huitron 2014), whereas higher concentrations confer resistance to oxidative stress (Leipnitz and Schumacher 2007). 3-HK can stimulate glutathione transferase, superoxide dismutase, and Nrf2, which are critical for antioxidant regulation. Therefore, changes in 3-HK concentration can modulate antioxidant systems and activate cellular redox sensors during inflammation. The generation of free radicals also enhances excitotoxic effects during the combined action of 3-HK and QA.

Quinolinic acid

QA represents a major downstream branch of KP metabolism that can contribute to oxidative stress, neuroinflammation, and excitotoxicity, providing a further link between altered KP activity and neuronal and glial dysfunction. Notably, QA acts as an agonist of NMDA receptors containing NR2A and NR2B subunits, promoting Ca²⁺ influx, activation of proteases, and the generation of ROS and nitrogen species, including superoxide (O₂⁻) and NO, which contribute to neurotoxicity (de Carvalho et al. 1996). In addition, QA can chelate Fe²⁺ ions, leading to lipid peroxidation (Chen et al. 2011). Furthermore, QA disrupts actin cytoskeleton dynamics in neurons and astrocytes, impairing intracellular protein transport necessary for maintaining synaptic homeostasis (Pierozan et al. 2015).

Beyond its direct excitotoxic action as an NMDA receptor agonist on neurons, QA activates glial cells and increases the production of chemokines such as monocyte chemoattractant protein-1 (MCP-1), as well as the expression of corresponding chemokine receptors, in a manner similar to pro-inflammatory cytokines including TNF-α, IL-1, and IFN-γ (Guillemin et al. 2003). Excessive QA also contribute indirectly to pathological post-translational modifications of tau protein by altering gene expression and reducing the activity of serine/threonine phosphatases in primary cultures of human neurons (Rahman et al. 2009). In human neurons and astrocytes, QA enhances the activity of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), resulting in cytotoxic and excitotoxic effects and triggering an energy crisis through NAD⁺ depletion. The NAD⁺ depletion activates the NAD⁺-dependent nuclear DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which, while attempting to restore energy homeostasis, can exacerbate cytotoxic damage when overactivated due to impaired energy levels and oxidative stress. Importantly, inhibition of iNOS and nNOS prevents these effects, highlighting the central role of NO in QA-mediated excitotoxicity (Maddison and Giorgini 2015).

In addition to activating NMDA receptors, QA stimulates the expression of several immunologically active and pro-inflammatory cytokines, including interleukin-8 (IL-8), CCL5, and macrophage inflammatory protein-1 (MIP-1), as well as multiple C-C and C-X-C chemokine receptors, such as CCR3, CCR5, CXCR4, and CXCR6 (Guillemin et al. 2005). These chemokines promote leukocyte recruitment across the BBB. In parallel, QA enhances glial cell proliferation while continuing to stimulate NMDA receptors, further contributing to neuroinflammatory and excitotoxic processes (Huang et al. 2020).

It is important to note that these metabolites do not function as independent mediators but are interconnected within the same metabolic pathway. Hence, the biological effect depends on the relative balance between the downstream neuroprotective and neurotoxic metabolic properties rather than on changes in the absolute concentrations of individual metabolites in the KP. For instance, in inflammatory responses, KP activity can alter metabolic flux between branches, changing the relative production of its downstream metabolites. This shift may influence mechanisms such as neuroinflammation, oxidative stress, or extracellular toxicity.

Xanthurenic and picolinic acid

Other downstream KP metabolites, including XA and PA, may further modify this balance through their antioxidant, immunomodulatory, and neurotransmitter effects. The roles of XA and PA are less well characterized, though they exhibit antioxidant and immunomodulatory effects via agonistic interactions with metabotropic glutamate receptors (mGluR2 and mGluR3). XA is produced through the transamination of 3-HK catalyzed by KAT II and has recently been shown to possess neurotransmitter activity in the nervous system (Sathyasaikumar et al. 2017).

PA promotes macrophage activation by upregulating IFN-dependent nitric oxide synthase and inducing MIP-1 expression. Intracranial, but not subcutaneous, administration of PA lowers seizure thresholds in mice, although the precise mechanism remains unclear (Cioczek-Czuczwar et al. 2017). PA can modulate glutamatergic neurotransmission depending on its concentration and the presence of other agonists such as kainates (Vrooman and Jhamandas 1993), and may exert anti-inflammatory and neuroprotective effects relevant to neuroinflammatory and neurodegenerative conditions.The overall neuroactive effects of KP downstream metabolites indicate that dysregulation depends on the relative balance among these metabolites.

Proteinopathies

A relatively large group of neurodegenerative diseases consists of proteinopathies including tauopathies, synucleinopathies, and amyloidoses (Delacourte 2005).

Proteinopathies represent a group of disorders associated with conformational changes in proteins. As a result of these conformational changes (misfolding of proteins), their function is altered, often leading to the formation of oligomers that can subsequently aggregate into pathological structures. A very important fact is that aggregated forms of misfolded proteins have the ability to induce the conversion of correctly folded proteins (Engelender et al. 2022). The individual stages of proper and improper protein folding are illustrated in Fig. 3.

Fig. 3.

Schematic representation of the different stages of correct and incorrect protein folding

Proteins most commonly fold in the cytoplasm; however, this process can also occur in mitochondria or the endoplasmic reticulum, which contains molecular chaperones. When intracellular proteins fail to fold efficiently, the cell activates the so-called “protein quality control system,” which can induce either refolding of the proteins or their degradation via molecular chaperones and proteasomes.

Tauopathies

Tauopathies represent a biochemically and morphologically heterogeneous group of neurodegenerative diseases. A characteristic feature of this group is the deposition—the formation of insoluble aggregates of abnormal (hyperphosphorylated) tau protein in the brain, primarily in neurons, glial cells, and the extracellular space. Tau protein, associated with microtubules (microtubule-associated protein tau; MAPT), binds to tubulin and promotes its polymerization and stabilization into microtubules (Lee and Leugers 2012).

Since tau protein was originally identified as a microtubule-associated protein, it is assumed that neurodegeneration results from the loss of tau’s ability to bind microtubules, which may occur due to hyperphosphorylation. Hyperphosphorylation is mediated by activated kinases capable of transferring phosphate groups to tau protein. Phosphorylated tau detaches from microtubules, aggregates, and forms neurofibrillary tangles (NFTs). Destabilized microtubules lose their signaling functions, which in some cases may lead to apoptosis (Ashrafian et al. 2021).

Another classification is based on the predominant tau isoforms present in aggregates: 3R tauopathies, 4R tauopathies, and 3R/4R tauopathies (with roughly equal 3R/4R ratios).

Amyloidoses

The origin of this group of diseases is the amyloid precursor protein (APP), which is encoded by a gene located on chromosome 21 (Pandey et al. 2016). APP is a transmembrane protein with three domains: intracellular, membrane-bound, and extracellular.

Under normal conditions, APP can be cleaved via two pathways: non-amyloidogenic and amyloidogenic. In the first pathway, APP is processed by α-secretase to generate a soluble fragment (sAPPα), which remains in the extracellular space, and an 83-amino-acid C-terminal fragment, which remains in the membrane. Subsequent cleavage by γ-secretase produces the non-amyloidogenic extracellular fragment (p3) and the APP intracellular domain (AICD).

In the second pathway, APP is cleaved by β- and γ-secretases. In the first step, β-secretase generates a C-terminal fragment, which is then cleaved by γ-secretase in the second step to produce an insoluble peptide known as amyloid-β (Aβ). The major final forms of Aβ are 38 amino acids (Aβ−38), 40 amino acids (Aβ−40), and 42 amino acids (Aβ−42) (Yiannopoulou and Papageorgiou 2020), with Aβ42 considered the most neurotoxic (Abeysinghe et al. 2020).

Neuronal damage occurs when an immune response is triggered, leading to inflammation. Additionally, deposition of Aβ plaques on blood vessels can result in angiopathy. The inflammatory response induced by Aβ and disruption of the BBB leads to the release of pro-inflammatory cytokines and chemokines. The cytokines secreted by brain immune cells can attract blood-derived immune cells that can infiltrate the brain due to increased permeability of the BBB (Gireud-Goss et al. 2021).

All three of these processes occur extracellularly, in contrast to tau pathology, which occurs intracellularly. The combination of these two pathological processes leads to the most well-known and prevalent amyloidosis: Alzheimer’s disease.

Synucleinopathies

Synucleinopathies are a group of progressive neurodegenerative disorders characterized by the abnormal accumulation of misfolded α-synuclein protein, leading to neuronal death. Major types include Parkinson’s disease, Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA), which cause motor, cognitive, and autonomic dysfunction. Clinically, they are characterized by a chronic and progressive decline in motor, cognitive, behavioural, and autonomic functions, depending on the distribution of the lesions. In PD and DLB, the protein is primarily found in Lewy bodies (LBs) within neurons, whereas in MSA, it is predominantly observed in glial cytoplasmic inclusions (GCIs) (Yang and Yu 2017). Neuron-derived α-synuclein activates microglia. It was shown that α-synuclein inclusions trigger microglial activation with increased expression of inflammation-related genes. Different α-synuclein conformations induce distinct inflammatory responses, including cytokine and chemokine production via TLR signaling (Stoll et al. 2024).

Taken together, these findings highlight that KP dysregulation may intersect with proteinopathies through direct effects mediated by kynurenine metabolites and indirect effects mediated by oxidative stress and neuroinflammatory processes. Downstream metabolites, such as 3-HK, have also been shown to modify amino acid residues in α-synuclein and Aβ, including lysine and histidine, thereby producing protein modifications (Capucciati et al. 2019). These interactions may alter protein structure and cause protein damage under oxidative conditions. QA provides another link between KP and protein aggregation. Studies have shown that QA can form amyloid-like fibrillar assemblies (Tavassoly et al. 2018). QA assemblies have also been shown to accelerate α-synuclein aggregation and may subsequently contribute to protein aggregation (Tavassoly et al. 2018). Inflammatory activation can also increase KMO-dependent metabolism toward downstream neurotoxic metabolites, leading to oxidative stress and neuronal dysfunction (Hayes et al. 2023). However, the temporal relationship between KP activation and oxidative injury remains unclear, and it is uncertain whether oxidative stress results from KP dysregulation. Additionally, neuroinflammation may influence the persistence of protein pathology and sustained microglial activation. In AD, 3-HK-related modifications have been linked to amyloid plaques and neurofibrillary tangles (Bonda et al. 2010). This may promote protein aggregation and impair protein homeostasis, although a direct correlation with protein aggregation has not been established. Furthermore, in AD, the relationship between QA and Aβ is bidirectional, as Aβ1–42 can induce IDO, thereby increasing the amount of QA available in microglia (Guillemin et al. 2003). Similarly, in Huntington’s disease, early disease shows increased QA and 3-HK, with 3-HK potentially exacerbating QA excitotoxicity (Guidetti et al. 2004). However, evidence linking this to direct Huntington aggregation remains limited. Overall, these findings suggest that KP dysregulation can overlap with proteinopathies, as direct metabolite-protein interactions, oxidative protein modification, impaired cellular homeostasis, and inflammatory processes may promote proteinopathy propagation. However, the association between metabolites and proteinopathies, as well as the direct effects demonstrated experimentally, would benefit from further investigation to assess their translational relevance.

Changes of the kynurenine pathway in selected neurological conditions

Parkinson’s disease

Parkinson’s disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of misfolded α-synuclein in Lewy bodies throughout the brainstem and other regions.The pathogenesis of PD is associated with disruptions in the ubiquitin-proteasome pathway, mitochondrial dysfunction, oxidative stress, and apoptosis (Dexter and Jenner 2013).

The first evidence associating the KP in PD pathogenesis came from studies using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vivo studies demonstrated that MPTP reduces KYNA synthesis and decreases the density of KAT I–positive neurons in the substantia nigra of mice, representing a chronic change associated with persistent dopaminergic degeneration (Knyihár-Csillik et al. 2006) However, KYNA pretreatment protects neurons and preserving mitochondrial function in cells exposed to MPP+ (Lee et al. 2008).

Moreover, disruptions in glutamate signaling, as shown in various animal models, can reduce the neuroprotective metabolite KYNA and contribute to PD development. Supporting this, in rodent 6‑OHDA models of PD, treatment with L‑KYN and probenecid elevates KYNA and dopamine levels, decreases glial activation and neuronal degeneration, and improves motor function, likely by preventing glutamate‑induced excitotoxicity through NMDA receptor inhibition (Zhang et al. 2019).

Excitotoxicity, oxidative stress, and inflammatory changes disrupt the KP, promoting the activation of its excitotoxic branches. This may result in a decrease in the metabolite KYNA and an increase in metabolite QA, which further exacerbates excitotoxicity and inflammatory response, contributing to the onset and progression of PD (Lim et al. 2017). Low endogenous KYNA levels directly impair the brain’s capacity to protect against QA- and glutamate-induced excitotoxicity through NMDA receptors (Beal et al. 1992). The pathway also enhances the production of 3-HK, ity that can promote free radicals during oxidative stress, which play an important role in PD pathogenesis. It was shown that high concentration of 3-HK can cause cell death by producing free radicals in PD (Okuda et al. 1998).

Alterations in KP metabolites have been detected in the brain tissue, plasma, and CSF of patients with PD. Compared to healthy controls, these patients exhibit a reduced KYNA/KYN ratio, elevated levels of QA and an increased QA/KYNA ratio. Overall, metabolomic studies indicate a shift in the kynurenine pathway toward enhanced production of the QA and reduced synthesis KYNA favoring excititoxic processes (Wilson et al. 2025).

Postmortem studies reported significanty decreased KYNA and KYN levels in frontal cortex, putamen, cerebellum and substantia nigra, while the concentration of the neurotoxin 3-HK in the striatum and SNpc was significantly increased and without change in TRP/KYN and KYN/KYNA ratios, in the brains of PD patients (Ogawa et al. 1992).

The disturbances of KYN pathway metabolites were measured as potential biomarkers in plasma as well as CSF (Chang et al. 2018). An increase in KYN/TRP ratio, depletion of plasma TRP level, and increase in KYN and KYNA were reported in serum samples of PD patients (Oxenkrug et al. 2017). Increase in serum KYNA was also observed among patients without dyskinesia, but not in dyskinetic PD patients (Chang et al. 2018). In contrast, the deficiency of KYNA was revealed in a metabolomic study performed on a larger cohort of PD patients. Findings included lower plasma KYNA/KYN ratio, higher QA level, and increased QA/KYNA ratio. PD subjects had increased levels of 3-HK and decreased amounts of 3-HAA acid in plasma (Heilman et al. 2020).

In PD patients was found increased neuroexcitatory QA/KYNA ratio in both plasma and CSF of PD participants associated with peripheral and inflammation and vitamin B₆ deficiency (Wilson et al. 2025). Similarly, lower KYNA, higher QA, and an elevated QA/PA ratio in CSF, as well as high 3-HK in plasma, were detected. Furthermore, elevated QA levels were associated with CSF tau, soluble TREM2 (sTREM2), and the severity of both motor and non-motor symptoms in PD. In addition, patient subgroups characterized by distinct KP profiles exhibited differences in clinical manifestations of the disease.

Compared to patients with healthy controls, individuals with PD exhibit a lower KYNA/KYN ratio, along with higher QA levels and an increased QA/KYNA ratio. Moreover, patients at an advanced stage of PD show further reductions in KYNA and the KYNA/KYN ratio, as well as elevations in QA levels and the QA/KYNA ratio, relative to those at an early stage and to healthy controls. In contrast, within advanced PD, KYNA and QA levels, as well as the KYNA/KYN and QA/KYNA ratios, do not differ significantly between patients with and without psychiatric symptoms, dementia, or levodopa-induced dyskinesia (Heilman et al. 2020).

KYNA analogues have been shown to suppress glutamatergic activity while also modulating NMDA receptor function, highlighting their therapeutic potential in PD. Improvement in motor symptoms has been observed in PD patients treated with zonisamide, a sulfonamide antiepileptic drug, although its precise mechanism of action remains unclear. Studies indicate that treatment with this ligand can promote the survival of dopaminergic neurons in a dose-dependent manner. Furthermore, FK506 significantly reduces the infiltration and activation of cytotoxic T cells, as well as various subtypes of macrophages and microglia (Liu et al. 2017a, b). These findings suggest that FK506 possesses anti-inflammatory properties and contributes to the reduction of neurodegeneration (Kou et al. 2025).

The inflammatory effects of KP activation may also intersect with purinergic signaling, further linking metabolic dysregulation to neuronal injury. In PD, adenosine A2A receptor signaling has been implicated in α-synuclein-associated neurotoxicity, neuroinflammatory processes, and oxidative stress. This complements the role of the KP in PD, where inflammatory cytokines can trigger IDO activation and the downstream KP metabolites play roles in neuroinflammation, oxidative stress, and excitotoxicity. This highlights a possible convergence in inflammatory and redox pathways between KP dysregulation and A2AR signaling in α-synuclein-associated neuronal injury and neurodegeneration (Rejili et al. 2026).

Alzheimer´s disease

AD is currently the most prevalent cause of dementia worldwide. AD pathology is characterized by the presence of amyloid-β plaques and neurofibrillary tangles in the brains of affected individuals. Despite extensive research, the underlying mechanisms of AD pathology remain incompletely understood.

Alterations in the KP in AD arise from a complex interplay of inflammatory, metabolic, and neurodegenerative processes. A major driver is chronic neuroinflammation, where activated microglia and astrocytes release pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ, which induce IDO1 and shift TRP metabolism toward KYN production (Campbell et al. 2014). This is further exacerbated by amyloid-β accumulation and tau pathology, which amplify inflammatory signaling and create a feed-forward loop promoting KP activation (Duan et al. 2020; Novoa et al. 2022). Dysregulation of key enzymes, including increased IDO1, tryptophan 2,3-dioxygenase (TDO), and KMO, drives metabolism toward metabolites such as 3-HK and QA, which may promote oxidative and excitotoxic processes, while potentially reducing the formation of the KYNA. Oxidative stress and mitochondrial dysfunction further modulate KP activity and contribute to redox imbalance and impaired energy metabolism. Together, these factors lead to an imbalance between neuroprotective and neurotoxic kynurenine metabolites, contributing to excitotoxicity, neuroinflammation, synaptic dysfunction, and ultimately cognitive decline in AD.

Alterations in the KP in Alzheimer’s disease remain complex, heterogeneous, and not entirely consistent across studies. Nevertheless, both peripheral and central levels of KP metabolites have been associated with disease severity and cognitive decline. Specifically, KYN (plasma, serum, and CSF), KYNA (serum, urine, CSF), TRP (plasma, serum, urine), the KYN/TRP ratio (plasma, serum, urine, CSF), and QA (plasma, CSF) have all been reported to correlate with cognitive impairment. Notably, positive correlations have been observed between cognitive performance and KYNA levels, whereas QA shows inverse associations, supporting the concept of a neuroprotective–neurotoxic balance within the KP. In contrast, some metabolites such as KYN, 3-HK, and AA exhibit only modest or non-significant changes (Gulaj et al. 2010).

A recent meta-analysis further highlighted compartment-specific alterations, showing decreased TRP levels exclusively in peripheral blood and an increased KYN/TRP ratio only in the periphery of AD patients. In the CSF, 3-HK levels were reduced and displayed greater variability in cognitively normal individuals compared to AD patients, KYNA was also decreased peripherally. Interestingly, no consistent differences were observed for KYN or QA between AD and control groups (Fernandes et al. 2023). These findings suggest that KP dysregulation in AD may differ between central and peripheral compartments, reflecting complex regulatory mechanisms.

Consistent with this, analyses of peripheral blood from AD patients revealed dysregulated levels of multiple KP metabolites, including KYN, 3-HK, KYNA, and QA, further implicating KP imbalance in AD pathophysiology. Moreover, studies measuring TRP, KYN, QA, and the KYN/TRP ratio in both plasma and CSF demonstrated significant correlations with core AD biomarkers such as amyloid-β and tau, linking KP metabolism directly to neurodegenerative processes (Bakker et al. 2023).

Metabolomic analyses provide further support, demonstrating significantly reduced serum TRP, KYN, and XA levels in AD patients, with XA positively correlating with cognitive scores such as the Mini-Mental State Examination (MMSE), reinforcing the link between KP metabolites and cognitive status (Whiley et al. 2021).

Overall, these findings support a significant, yet complex involvement of the KP in AD pathogenesis, highlighting both neurotoxic and neuroprotective mechanisms. This dual role makes the KP an attractive target for therapeutic intervention. Accordingly, various strategies have been explored to either enhance endogenous KYNA levels or reduce the production of neurotoxic metabolites such as QA. In animal models of AD, such approaches have shown promise in slowing disease progression (Majerova et al. 2022). Furthermore, recent experimental work demonstrated that chronic administration of the KYNA analogue KYNA-1 modulates tau pathology and reduces neuroinflammation in a rat model of tauopathy (Majerova et al. 2022).

Taken together, the growing body of evidence suggests that KP dysregulation is intricately linked to neuroinflammation, metabolic imbalance, and neurodegeneration in AD, and may represent a promising avenue for the development of novel diagnostic biomarkers and therapeutic strategies.

Therapeutic potential and translational challenges

KP metabolites such as KYN, KYNA, 3-HK, and QA provide information on alterations in tryptophan metabolism and on the balance between neuroprotection and neurotoxicity in the KP (Pathak et al. 2024). However, individual metabolites do not necessarily show the same direction or magnitude of change across different diseases. Metabolic alterations may vary by disease type, disease stage, tissue sample, and individual patient characteristics, limiting the confidence with which a given KP metabolite can act as a diagnostic biomarker (Pathak et al. 2024). Studies on PD further show the value of incorporating complementary biological processes. For example, adenosine A2A receptor signaling has been linked to neuroinflammatory and oxidative mechanisms involving α-synuclein, while dysregulated leukotriene signaling has been linked to oxidative stress, mitochondrial dysfunction, and inflammatory signaling (Alshahrani et al. 2025; Rejili et al. 2026). These pathways highlight inflammation and cellular stress responses, while KP metabolites provide information on metabolic responses, all in association with neuronal injury and neurodegeneration. This suggests that KP-derived metabolites are most informative when interpreted alongside markers of inflammation and oxidative injury. This could allow identification of which component of the overall pathological process each marker represents, providing a more comprehensive view of how KP activity contributes to neuronal injury.

Furthermore, KP-targeting as a therapeutic strategy has several limitations. KP has both neurotoxic and neuroprotective effects, so broad pathway inhibition could eliminate beneficial metabolic functions. For example, inhibiting KMO could shift pathway metabolism to other branches rather than inhibiting KP (Chen et al. 2022). Additionally, KP metabolites have physiological functions, so altering their concentrations may extend beyond the intended neuroprotective effects. Therefore, selective modulation could be preferable to complete pathway inhibition. It is also important to note that there is limited evidence for KMO inhibition and KYNA-related approaches in clinical studies and translational applications. Most findings are experimental (Pocivavsek et al. 2024). Furthermore, a key translational issue is determining which metabolite to target and at what stage of the disease. KP alterations are highly heterogeneous across diseases, meaning that a single therapeutic pathway or target is unlikely to yield replicable effects in other diseases (Pathak et al. 2024). KP-targeting approaches are mainly oriented toward influencing metabolic pathway activity and the neurotoxic and neuroprotective balance, whereas A2AR and inflammatory targeting approaches primarily target inflammatory and oxidative signaling pathways associated with neuronal injury. KP-targeting approaches and anti-inflammatory, neuroprotective approaches may have complementary effects in neuronal injury. However, this is a theoretical possibility that requires further exploration.

The differential involvement of metabolites in Tau, Aβ, and α-synuclein neuropathology, together with their potential therapeutic implications, is summarized in Table 1.

Table 1.

Comparative involvement of the kynurenine pathway in major proteinopathies

Protein pathology	Representative disorders	KP metabolites implicated	Principal pathological mechanism	Possible therapeutic implication
Tau	AD; primary tauopathies	QA, KYNA	• QA-associated tau phosphorylation • Excititoxicity • Oxidative stress	• KYNA analogues • Reduction of QA mediated toxicity
Aβ	AD; amyloidoses	KYN, KYNA, 3-HK, QA	• KP imbalance associated with AB pathology • Oxidative stress • Neuroinflammation	• increase KYNA availability • reduced neurotoxic KP metabolites • KYNA/LKYN analogues
α-Synuclein	PD; DLB; MSA	KYNA, QA, 3-HK	• ↓ KYNA/↑ QA and 3-HK • Excititoxicity • Oxidative stress • Neuroinflammation	• increase KYNA availability • KYNA analogues • LKYN + probenecid

Heatstroke

Heatstroke is a severe clinical consequence of heat stress, characterized by an elevation of core body temperature above 40 °C with CNS dysfunction (Yoneda et al. 2024). It represents the most severe form of heat-related illness (HRI) and is associated with systemic inflammation, oxidative stress, BBB disruption, and metabolic dysregulation, and shown to contribute to neuronal and glial injury. Heatstroke effects may also persist beyond the acute phase, commonly presenting with neurological sequelae (Epstein and Yanovich 2019; Yoneda et al. 2024).

Pathomechanisms in heatstroke, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and excitotoxicity, are also implicated in proteinopathies, alongside disruption of protein homeostasis, which promotes protein misfolding, protein aggregation, and neuronal injury (Pérez-De La Cruz, Carrillo-Mora et al. 2012, Tavassoly et al. 2018). This indicates that heatstroke and proteinopathies share several molecular and cellular pathomechanisms, raising the question of whether pathways involved in acute heat injury also contribute to protein pathology.

The KP may function as a pathway within this shared biological response. Heatstroke-associated inflammation, driven by pro-inflammatory cytokines such as IFN-γ, IL-1β, IL-6, and TNF-α, can promote IDO activity. This increases the conversion of TRP to KYN and the production of downstream metabolites such as KYNA, PIC, 3-HK, and QA. However, the effects of these metabolites are context-dependent, with compounds such as QA and 3-HK commonly associated with excitotoxicity and oxidative stress (Pérez-De La Cruz, Carrillo-Mora et al. 2012, Majerova et al. 2026). Hence, KP metabolites may interact with processes present in both heatstroke and proteinopathies (Fig. 4).

Fig. 4.

Proposed mechanistic link between heatstroke kynurenine pathway activation, and protein pathology. Heat stress may induce IDO/TDO and promote the release of pro-inflammatory cytokines, activating the kynurenine pathway and altering tryptophan metabolism. This may increase the availability of kynureine and downstream neuroactive metabolites of the KP, contributing to excitotoxicity, neuroinflammation, and oxidative stress. This may result in protein misfolding and aggregation involving tau, Aβ, α-Synuclein, and huntingtin, leading to neuronal injury and potential protein pathology. Heatstroke, resulting from heat stress and failure of the body’s compensatory mechanisms, may result in multiple organ failure

Although the KP is increasingly recognized as a stress-response pathway, direct evidence linking KP dysregulation to heatstroke remains limited. Recent evidence, however, has identified alterations in KP metabolism after heat exposure, highlighting a potential role for the KP in the response to heat stress. A recent experimental study in a murine model showed alterations in KP metabolites in both plasma and the brain following heatstroke (Majerova et al. 2026). Similarly, a recent human study showed alterations in KP metabolites, including KYNA, PIC, QA, and 3-HK after thermal stress. These alterations did not persist and returned toward baseline during recovery, suggesting that KP activation can be an adaptive and reversible response to physiological thermal stress (Louvrou et al. 2025). However, the study examined controlled hyperthermia rather than clinical heatstroke, so it remains unclear whether the metabolic consequences of KP activation differ in clinical heatstroke.

Taken together, heatstroke–associated inflammatory and oxidative processes may activate the KP, amplifying neuronal injury and impairing protein homeostasis. The KP may therefore serve as a link between heatstroke and protein-pathology pathways.

The proposed mechanism is further supported by evidence highlighting the persistence of neurological consequences of heatstroke beyond acute phase. Studies have shown that neurological abnormalities after heatstroke persist for several weeks during recovery, with loss of Purkinje cells and synaptic impairment, while clinical reports have documented persistent neurological sequelae (Miyamoto et al. 2022; Yoneda et al. 2024). However, the role of the KP in long-term neurological effects following heatstroke is still unclear.

Conclusions

In conclusion, the overlap in mechanisms underlying heatstroke and proteinopathies highlights the central nervous system’s shared vulnerability to proteotoxic, inflammatory, and metabolic stress. Acute hyperthermia induces processes such as protein misfolding, oxidative damage, and neuroinflammation that closely mirror those observed in chronic neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. The involvement of the KP further suggests a potential link between systemic stress responses and neurodegenerative cascades. However, direct evidence linking KP dysregulation after heat stress to persistent protein pathology remains limited. These insights suggest that KP may represent a common mechanistic link through which heat stress may not only trigger an acute neurological insult but also act as a potential modifier or accelerator of proteinopathic processes, warranting further investigation into its long-term neurological consequences and therapeutic targeting of shared pathways.

Future studies should establish whether KP alterations persist in clinical heatstroke, and experimental studies should further investigate whether KP modulation or dysregulation directly affects amyloid-β, α-synuclein, and tau pathology following heat stress. Studies targeting IDO1, KMO, or KATs should consider the balance of downstream KP metabolites and their context–dependent effects. However, clinical translation remains challenging due to disease heterogeneity, metabolic functions, and treatment timing.

Abbreviations

AA

Anthralinic acid

Aβ 

Amyloid Beta

AD

Alzheimer’s disease

AhR

Aryl hydrocarbon receptor

ALS

Amyotrophic lateral sclerosis

AFMK

N-acetyl-N-formyl-5-methoxykynurenamine

BBB

Blood-brain barrier

CCL1

C-C motif chemokine ligand 1

CCL5

C-C motif chemokine ligand 5

CCR3

Chemokine receptor 3

CCR5

Chemokine receptor 5

CNS

Central nervous system

CSF

Cerebralspinal fluid

CXCR4

C-X-C chemokine receptors 4

CXCR6

C-X-C chemokine receptors 6

DLB

Dementia with Lewy bodies

IDO (IDO1)

Indoleamine 2,3-dioxygenase

IFN-γ 

Interferon-gamma

IL-1β

Interleukin-1β

IL-6

Interleukin-6

IL-8

Interleukin-8

KAT

Kynurenine aminotransferase

KMO

Kynurenine 3-monooxygenase

KP

Kynurenine pathway

KYN

Kynurenine

KYNA

Kynurenine acid

LAT1

L-type amino acid transporter 1

LNAA

Large neutral amino acid

MCP-1

Monocyte chemoattractant protein-1

MEL

Melatonin

MIP-1

Macrophage inflammatory protein-1

MSA

Multiple system atrophy

NA

Nicotinic acid

NAD⁺

Nicotinamide adenine dinucleotide

NAS

N-acetylserotonin

NMDA

N-methyl-D-aspartate

NO

Nitric Oxide

nNOS

Neuronal nitric oxide synthase

iNOS

Inducible nitric oxide synthase

PA

Picolinic acid

PARP-1

Poly(ADP-ribose) polymerase-1

PD

Parkinson’s disease

QA

Quinolinic acid

ROS

Reactive oxygen species

SNpc

Substantia nigra pars compacta

SP

Serotonin pathway

TDO

Tryptophan 2,3-dioxygenase

Author contributions

Conceptualization was carried out by D.W.; the original draft was prepared by D.W., P.M., and A.K; review and editing were performed by A.K. All authors have read and approved the final version of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.