Multi-omics analysis reveals the mechanism of action of Atractylodin against depression.

Atractylodin (ATR) is a natural sesquiterpene compound primarily isolated from the rhizomes of Atractylodes, a plant of the Asteraceae family. It is the core bioactive component of the traditional Chinese medicine Atractylodes and has been confirmed to possess anti-inflammatory, antioxidant, and neuroregulatory functions in various disease models. Recent studies have highlighted ATR's significant roles in anti-tumor, anti-inflammatory, and immune-regulatory activities. However, it remains unclear whether ATR can alleviate depression and its potential pharmacological mechanisms. Our study demonstrates that ATR treatment alleviated depression-like behaviors and improved neuronal changes in the hippocampus of rats. Transcriptomic and proteomic analyses revealed that ATR exerted its antidepressant effects primarily through the regulation of ferroptosis and synaptic plasticity. ATR increased the expression of IL-10, SOD, and GSH, while reducing IL-1β, TNF-α, MDA, and ROS levels, thereby improving inflammation and oxidative stress. Immunohistochemical results indicated that ATR treatment significantly increased the expression of GPX4, SLC7A11, BDNF and NRF2 proteins. This study demonstrates that ATR significantly alleviates depressive symptoms in CUMS rats, with its mechanism primarily involving the regulation of ferroptosis and improvement of synaptic plasticity. ATR may be a potential candidate as an antidepressant.