Hierarchical Disruption of the Tryptophan–Melatonin Axis Contributes to Glioma Progression Through AKT / ERK / STAT3 Signalling

Melatonin signalling, mediated by membrane receptors and tightly regulated biosynthetic enzymes, is a key component of circadian and neuroendocrine control in the brain. However, whether the tryptophan-melatonin axis remains hierarchically intact during glioma progression and how its disruption affects downstream signalling remain unclear. In this study, transcriptomic data from TCGA, CGGA, and GTEx were integrated to characterize the expression patterns of melatonin receptors (MTNR1A and MTNR1B) and biosynthetic enzymes (AANAT and ASMT) across normal brain tissue, lower-grade glioma and glioblastoma. Protein expression was validated by immunohistochemistry, and functional consequences were investigated through gain- and loss-of-function experiments in glioma cells, followed by proliferation, migration, invasion, apoptosis and signalling analyses. Multi-layered analyses revealed a coordinated disruption of the tryptophan-melatonin axis during glioma progression. Expression of AANAT, ASMT, MTNR1A and MTNR1B progressively declined with increasing tumour grade and was associated with poor prognosis. Immunohistochemistry confirmed reduced MTNR1A and ASMT protein expression in glioma tissues. Restoration of these factors suppressed glioma cell proliferation, migration and invasion while promoting apoptosis. Mechanistically, these effects were accompanied by inhibition of AKT, ERK and STAT3 signalling. These findings demonstrate that hierarchical disruption of receptor- and synthesis-dependent melatonin signalling is a defining molecular feature of glioma and may contribute to malignant progression through activation of AKT/ERK/STAT3 pathways, providing new insights into the biological and therapeutic relevance of the tryptophan-melatonin axis in glioma.