Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism. Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation. Here, we report celastrol, a traditional Chinese medicine, can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation. Mechanistically, celastrol binds to adenylyl cyclase associated protein 1 (CAP1) and inhibits the interaction between CAP1 and resistin, which restrains the cyclic adenylate monophosphate (cAMP)eprotein kinase A (PKA)enuclear factor kappa-B (NF-kB) signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome. Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity. In contrast, overexpression of CAP1 in macrophages aggravated inflammation. Taken together, our study identifies celastrol, which directly targets CAP1 in macrophages, might be a promising drug candidate for the treatment of inflammatory metabolic diseases, such as metabolic syndrome.