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Background Ulcerative colitis (UC), as a chronic and idiopathic inflammatory disorder of colonic mucosa, remains a significant global health challenge, with current therapeutic strategies often providing insufficient long-term efficacy and accompanied by adverse side effects. Emerging evidence indicates that macrophage lipid metabolism and polarization play pivotal roles in UC pathogenesis, highlighting the need for novel therapeutic agents targeting immunometabolic dysregulation.Methods Kushenol A (KA), a natural flavonoid derived from Sophora flavescens, was identified through high-content screening. Its therapeutic efficacy was evaluated in dextran sulfate sodium–induced and IL-10 -/- murine colitis models. Single-cell RNA sequencing was performed to characterize PPARγ expression in intestinal macrophages from UC patients and healthy controls. Molecular docking, cellular thermal shift assay, and microscale thermophoresis were used to validate the interaction between KA and PPARγ.Results KA administration significantly ameliorated colitis, prevented pathogenic dyslipidemia, and promoted M2 macrophage polarization in vivo. scRNA-seq analysis revealed markedly reduced PPARγ expression in intestinal macrophages from UC patients. Mechanistically, KA activated the PPARγ–ABHD5 signaling pathway, restoring lipid droplet homeostasis by enhancing lipolysis of aberrantly accumulated lipids. Biophysical assays confirmed that KA directly binds to PPARγ and enhances its transcriptional activity, leading to upregulation of ABHD5. Clinically, KA intake was negatively correlated with disease activity and positively associated with PPARγ and ABHD5 expression in UC patients ( IDDF2026-ABS-0091 Figure 1).Conclusions These findings identify Kushenol A as a promising therapeutic candidate for UC by targeting macrophage immunometabolic reprogramming via direct activation of the PPARγ–ABHD5 axis.Abstract IDDF2026-ABS-0091 Figure 1