Gut-derived IL-17A via STAT3/RORγt signaling underlies sleep disruption-induced depression: Targeting effects of Schisandrin B therapy.

Abstract

BACKGROUND: Circadian rhythm disruption and chronic sleep deprivation are increasingly recognized as key contributors to depression, largely through gut-brain axis dysregulation and neuroinflammatory activation. IL-17A, a pro-inflammatory cytokine primarily derived from intestinal Th17 cells, has emerged as a pivotal mediator linking gut immune imbalance to central nervous system dysfunction. PURPOSE: This study aimed to elucidate the gut-derived IL-17A-STAT3/RORγt signaling mechanism underlying sleep-deprivation-induced depression and to determine whether Schisandrin B, a lignan from Schisandra chinensis, can alleviate depressive phenotypes by restoring gut-brain axis homeostasis. METHODS: Clinical analyses of plasma cytokines and metabolites were integrated with a mouse model of sleep-deprivation-induced depression. Behavioral tests, resting-state fMRI, gut microbiota 16S rDNA sequencing, Western blotting, ELISA, and network pharmacology with molecular docking were employed to comprehensively investigate neuroimmune, microbial, and neurofunctional alterations. RESULTS: Patients with circadian rhythm disorder-related depression exhibited elevated IL-17A and systemic inflammatory cytokines, accompanied by metabolic dysregulation. Sleep-deprived mice showed depressive-like behaviors, intestinal barrier disruption, Th17/IL-17A pathway activation, and abnormal RS-fMRI activity in mood-regulating brain regions. Schisandrin B treatment markedly reversed these changes-restoring gut microbial balance, enhancing barrier integrity, suppressing IL-17A-driven inflammation, and normalizing neural function. Mechanistically, Schisandrin B inhibited STAT3 phosphorylation and RORγt expression, while targeting MAPK1 and GSK3β as key regulatory nodes. CONCLUSION: This study identifies gut-derived IL-17A-STAT3/RORγt signaling as a mechanistic bridge between sleep deprivation and neuroinflammation, providing direct evidence for the immunological basis of circadian rhythm-related depression. By integrating multi-omics and neuroimaging validation, we demonstrate for the first time that Schisandrin B exerts antidepressant-like effects via coordinated modulation of the gut-brain-immune network. These findings highlight Schisandrin B as a promising natural immunomodulatory candidate for the treatment of mood disorders associated with disrupted circadian rhythms.