Network pharmacological analysis and animal experiment verification of SAL inhibiting the IL-17 signaling pathway in the treatment of depression

Depression is a prevalent and severe mental disorder. Recently, the “Gut-Brain Axis” theory has offered a novel perspective on its pathophysiological mechanisms. As a major bioactive constituent isolated from Rhodiola rosea L., Salidroside (SAL) possesses well-documented anti-stress, antioxidant, and neuroprotective activities. Based on the gut-brain axis hypothesis, the present work evaluated whether SAL exerts antidepressant-like actions in a murine model of chronic unpredictable mild stress (CUMS) and further clarified its potential molecular mechanisms. During the establishment of the CUMS model, mice received intragastric SAL at doses of 25 mg·kg −1 and 50 mg·kg −1 daily for 4 weeks. Behavioral experiments evaluated anxiety and depressive-like behaviors, while gastrointestinal function changes were monitored. Results indicated that SAL significantly alleviated depressive-like behaviors, restored gastrointestinal function and structure, increased serotonin expression in the gut-brain axis, and repaired hippocampal neural damage. RNA sequencing of hippocampal tissue suggested that SAL inhibited abnormal IL-17 signaling pathway activation. Western blot analysis confirmed that SAL reduced IL-17 levels in hippocampal tissue and inhibited excessive phosphorylation of downstream p-MAPK and p-NF-κB. Additionally, SAL intervention restored the disrupted intestinal flora in depressed mice. Spearman correlation analysis showed that changes in bacterial genera such as Rikenella , Oscillibacter , and Barnesiella might be crucial in SAL's regulation of the gut-brain axis and its antidepressant effects. In summary, this study documented the ameliorative effects of SAL on depressive-like behaviors in CUMS model mice, as well as its impact on the gut-brain axis and the IL-17 signaling pathway. These observations may serve as a reference for future research on SAL as a functional food ingredient.