Gastrointestinal diseases and disorders (GIDD) are often comorbid with mental disorders, including depression, anxiety, cognitive impairment and so on. Repairing intestinal mucosal injury is an effective strategy to prevent exogenous substances from entering the blood circulation, thus mitigating neuroinflammation and subsequent psychiatric symptoms. Our study revealed that syringin, an active ingredient derived from traditional Chinese medicine, can markedly alleviate intestinal barrier damage induced by radiation, chemotherapeutic agents and dextran sulfate sodium (DSS), as well as intestinal injury-related cognitive deficits and anxiety-like behaviors. To further explore the potential targets responsible for its intestinal protective effects, we performed target screening via limited proteolysis-coupled mass spectrometry (LIP-MS).