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• BAI treatment delayed the onset of EAE, alleviate clinical symptoms, demyelination and inflammatory cell infiltration. • BAI inhibited the overactivation of M1 microglia/macrophages in vivo and in vitro, significantly decreased the expression of proinflammatory cytokines in M1 microglia/macrophages. • BAI has the binding ability to the SH2 domain of STAT1, and leaved P-STAT1 in the cytoplasm rather than transferred to the nucleus during inflammatory stimulation. Microglia/macrophage polarization modulation plays a key role in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). M1 microglia/macrophages secrete a variety of cytokines that cause inflammation and facilitate demyelination in the central nervous system (CNS). Baicalein (5,6,7-trihydroxyflavone, C 15 H 10 O 5 , BAI), a natural flavonoid isolated from the roots of the traditional Chinese medicine Scutellaria baicalensis Georgi, has been suggested to have a wide range of biological effects, including antioxidant, anti-inflammatory, and neuroprotective properties. In this study, flow cytometry, Western blotting, immunofluorescence and other methods were used to investigate whether BAI could reduce the demyelination and inflammatory response of the spinal cord in EAE mice induced by MOG 35-55 and affect the polarization of spinal microglia/macrophages. Our results showed that BAI treatment delayed the onset of EAE and alleviated clinical symptoms, demyelination and inflammatory cell infiltration. Meanwhile, BAI inhibited the overactivation of M1 microglia/macrophages in vivo and in vitro, significantly decreased the expression of proinflammatory cytokines in M1 microglia/macrophages, and inhibited the activation of STAT1. Subsequently, molecular docking, pull-down and immunofluorescence experiments confirmed that BAI has the ability to bind to the SH2 domain of STAT1 and that BAI colocalizes with p-STAT1 in the cytoplasm rather than being transferred to the nucleus during inflammatory stimulation. This study showed that BAI might inhibit the polarization of microglia/macrophages to the M1 phenotype in EAE mice by targeting STAT1. This new discovery lays a theoretical and experimental foundation for the clinical application of BAI in the treatment of MS. [ABSTRACT FROM AUTHOR]