Scope: The purpose of this research is to investigate the specific role of HSP90 paralogs in ulcerative colitis (UC), and to explore the mechanisms behind the inhibitory effects of galangin (Gal) on UC by inhibiting HSP90π· in vivo. Methods and results: In order to achieve this, publicly available gene expression data and molecular biology techniques are used. The results show that the expression of HSP90π· is significantly increased in the mucosal biopsies of UC patients and in the colons of colitis mice, and that there is a significant correlation between HSP90π· levels and disease severity. Then, Gal is found to bind directly to HSP90π· and downregulates the level of p-AKT, as well as the stability and oligomerization of HSP90π·, indicating Gal as an HSP90π· inhibitor. Moreover, the findings reveal that HSP90π· plays a critical role in controlling UC, and that Gal can alleviate colitis by inhibiting HSP90π· and perturbing fatty acid synthesis-mediated NLRP3 inflammasome activation. Conclusion: These results not only provide insight into the potential therapeutic use of Gal in the treatment of UC, but also offer new perspectives on the role of HSP90π· in this disease.