Investigating the Role and Underlying Mechanisms of 18β-Glycyrrhetinic Acid in the Therapy of Ulcerative Colitis Through Modulation of the PPAR-γ/NF-κB Signaling Pathway

Aijing Zhu,1,* Qingqing Qiu,1,* Zhengguang Xu,1,* Qilian Zhang,2 Fang Sun,1,3 Yanzhan Liu,1 Zeang Chen,1 Yanan Zhang,4 Jing Yao1,3 1School of Basic Medicine, Jining Medical University, Jining, 272067, People’s Republic of China; 2People’s Hospital Affiliated to Shandong First Medical University, Jinan, 271100, People’s Republic of China; 3Jining Key Laboratory of Pharmacology, Jining Medical University, Jining, 272067, People’s Republic of China; 4Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Yao, Jining Medical University, School of Basic Medicine, Jining Medical University, Jining, 272067, People’s Republic of China, Tel +86 537-3616269, Email [email protected] Yanan Zhang, Affiliated Hospital of Jining Medical University, Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272029, People’s Republic of China, Tel +86 15153705143, Email [email protected]: 18β-glycyrrhetinic acid (18β-GA), a triterpenoid saponin naturally occurring in Glycyrrhizae uralensis, has potent anti-inflammatory and antioxidant properties, but the therapeutic efficacy and precise mechanism of 18β-GA in ulcerative colitis (UC) remain unclear.Methods: To determine the therapeutic potential of 18β-GA, we constructed a dextran sodium sulfate (DSS)-induced UC model on a cohort of thirty-two female BALB/c mice and used mouse peritoneal macrophages to establish a co-culture system for in vitro experiments. We measured body weight, fecal characteristics, colon length, disease activity index (DAI) of mice, and the degree of colonic histological lesions. Changes in the composition of intestinal flora were monitored using high-throughput 16S rDNA sequencing. Combining network pharmacology and molecular docking to predict pharmacological mechanisms and using Western blot for validation.Results: 18β-GA significantly alleviated DSS-induced weight loss, colon length reduction, an increase in the DAI score, and pathological colon damage. Additionally, 18β-GA promotes a favorable environment that hindered the proliferation of pathogenic bacteria, thereby promoting gut health. Co-culture and scratch assays confirmed that 18β-GA promotes mucosal repair. Network pharmacology and molecular docking predicted potential drug targets, while Western blot analysis revealed that 18β-GA downregulated phosphorylated nuclear factor kappa-B (p-NF-κB) and activated the peroxisome proliferator-activated receptor γ (PPAR-γ).Conclusion: The therapeutic application of 18β-GA in UC demonstrates a multifaceted pharmacological process. It fosters harmonious intestinal microbiota, reinstates the integrity of the intestinal barrier, and exerts its beneficial effects through modulating the PPAR-γ/NF-κB signaling pathway, underscoring its potential as a therapeutic agent for UC.Keywords: 18β-GA, ulcerative colitis, 16S rDNA sequencing, PPAR-γ/NF-κB signaling