The active ingredient Monotropein in Morinda officinalis alleviates neuroinflammation via inhibition the cGAS/STING signaling pathway

Ethnopharmacological relevance ： Neuroinflammation is recognized as a key pathological mechanism in the onset and progression of depression. Inhibiting neuroinflammation represents a promising strategy for effective depression treatment. Monotropein (Mon), a major bioactive cyclohexene ether terpene glycoside extracted from Morinda officinalis, a medicinal and edible herb, exhibits potent anti-inflammatory activity.Aim of the study ： This study aims to investigate the antidepressant-like effects of Mon in a lipopolysaccharide (LPS)-induced mouse model of depression and to further elucidate the underlying molecular mechanisms.Results  ：Our studies indicated that FXT and Mon significantly reversed LPS-induced depressive-like behaviors, mitigated hippocampal tissue and neuronal damage, reduced pro-inflammatory cytokine levels (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-β) in the hippocampus, and inhibited activation of microglia and astrocytes. Transcriptome sequencing revealed that Mon primarily modulated the cGAS/STING pathway and downstream inflammation-related gene expression. qPCR and Western blot analyses also confirmed that Mon markedly suppressed the expression of genes and proteins in the cGAS/STING signaling pathway. Furthermore, co-treatment with the STING pathway inhibitor C176 significantly attenuated Mon’s therapeutic effects on LPS-induced neuroinflammation and depressive-like behaviors.Conclusions ：Our findings indicate that Mon significantly ameliorates LPS-induced depressive-like symptoms in mice, potentially through inhibition of the cGAS/STING signaling pathway.