Oleanolic acid alleviates ulcerative colitis by remodeling Th17 cells via targeting HSP90β-ODC1 pathway-mediated...

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease (IBD) characterized by chronic inflammation of the colon and rectum. Its pathogenesis is closely associated with dysregulated mucosal immune responses and intestinal barrier dysfunction. Although oleanolic acid (OA), a natural pentacyclic triterpenoid, has shown therapeutic potential for UC, its precise molecular targets and underlying mechanisms remain poorly understood.

This study aimed to investigate the therapeutic effects and molecular mechanisms of OA in dextran sulfate sodium (DSS)-induced colitis in mice, with a specific focus on intestinal Th17 cell modulation and polyamine biosynthesis.

A DSS-induced colitis model was established in mice and treated with OA. Therapeutic efficacy was assessed through DAI scoring, histopathology, and barrier integrity analysis. Intestinal Th17 cell subsets were characterized by flow cytometry and gene expression profiling. Polyamine biosynthesis was evaluated by Western blot and targeted metabolite detection. Bioinformatics and AAV-mediated overexpression models were used to explore the role of the HSP90β-ODC1 pathway in OA-mediated Th17 remodeling. SPR and Lip-MS were employed to assess the potential of HSP90β as an OA target. In vitro, naïve (CD44⁻CD62L⁺) T cells were isolated from mouse spleens and induced to differentiate into pathogenic/non-pathogenic Th17 subsets to validate OA's effects on Th17 differentiation and polyamine biosynthesis.

OA treatment significantly ameliorated DSS-induced colitis, as evidenced by improved body weight, disease activity index, colon length, and histopathology. OA also restored disrupted chemical and epithelial barriers. Mechanistically, OA remodeled intestinal Th17 cell subsets by suppressing their pathogenic traits and enhancing anti-inflammatory phenotypes. This effect was mediated through the inhibition of polyamine synthesis-related pathways in Th17 cells. Notably, bioinformatic and pharmacological analyses identified the HSP90β-ODC1 axis as a key pathway downregulated by OA. Overexpression of HSP90β both in vitro and in vivo partially reversed OA's modulatory effects on Th17 cell subtypes and polyamine biosynthesis.

This study demonstrates that OA alleviates DSS-induced colitis by reshaping intestinal Th17 subsets and restoring mucosal immune balance via suppression of polyamine synthesis, with the HSP90β-ODC1 pathway as a key mediator. These findings support OA as a promising therapeutic agent for mucosal immunomodulation and intestinal barrier protection in UC.