Myasthenia gravis (MG) is a rare autoimmune disorder traditionally characterized by motor symptoms, while nonmotor symptoms like anxiety, insomnia, and memory impairment have received less attention due to the complexities of brain-related studies. Leflunomide (LEF), a frontline medication for rheumatoid arthritis, has shown high efficacy in treating both motor and nonmotor symptoms of MG in our decade-long clinical research. This study aimed to explore the therapeutic mechanisms of LEF, particularly its metabolites' actions in the brain. We employed spatial metabolomics (SM) and 4D-DIA proteomics to identify LEF's key active metabolite. These metabolites play pivotal roles in constructing the metabolic pathway maps that support LEF's mechanism of action. We aimed to find the key protein affecting MG's nonmotor symptoms.