Chronic stress has profound effects on the body, driven in part by dysregulation of neuroendocrine systems such as cortisol signalling. Elevated cortisol levels have been associated with neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, as well as cardiovascular and metabolic disorders. Chronic stress also impacts the immune system, increasing susceptibility to infections and potentially contributing to autoimmune disease. This is particularly relevant given the rising prevalence of mental health conditions worldwide. Against this backdrop, a recent study from Professor Xiaohong Liang’s group investigates the mechanistic link between chronic stress and liver disease.
In this study, they demonstrate that chronic stress promotes hepatocellular carcinoma progression. Mice exposed to chronic stress exhibited increased tumour burden and an increased mortality rate compared to controls. This effect was dependent on CD8⁺ T cells, as depletion of these cells abolished the difference in tumour progression between stressed and control animals.
Given the liver’s central role in metabolism, the authors performed untargeted metabolomic profiling to assess stress-induced metabolic changes. Notably, tryptophan metabolism emerged as the most significantly affected pathway. Further analyses revealed that chronic stress shifts the kynurenine pathway, increasing kynurenic acid levels while reducing nicotinamide (NAM) and nicotinic acid, key intermediates in NAD⁺ synthesis.
Importantly, pharmacological intervention targeting this pathway, specifically inhibition of kynurenic acid signalling via the aryl hydrocarbon receptor (AHR) combined with NAM supplementation, reduced tumour burden and restored immune function. Mechanistically, the study identifies sympathetic nervous system signalling, via the β2-adrenergic receptor (ADRB2), as a key upstream regulator of hepatic tryptophan metabolism under stress conditions.
Taken together, this work highlights a neuroendocrine–metabolic–immune axis linking chronic stress to cancer progression and identifies the kynurenine pathway as a potential therapeutic target to improve outcomes in hepatocellular carcinoma. It will be particularly interesting to explore whether stress-induced alterations in tryptophan metabolism represent a broader, system-level mechanism influencing cancer progression beyond hepatocellular carcinoma.