Chen Wei, Shan Yunan, Wang Meng, Liang Rui, Sa Ri
Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China.
Br J Pharmacol. 2025 Oct;182(20):4968-4983. doi: 10.1111/bph.17354. Epub 2024 Oct 22.
Chicoric acid, a hydroxycinnamic acid, exhibits anti-inflammation activities. However, the specific mechanisms underlying the effects of chicoric acid on dextran sulfate sodium (DSS)-induced colitis remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the protective effects of chicoric acid in DSS-induced colitis.
Mice with DSS-induced colitis (UC mice) were treated for a week with chicoric acid. Symptoms of colitis, colonic pathology, inflammation-related indicators, and intestinal mucosal barrier function were evaluated. RNA sequencing was performed on colon tissues to obtain differentially expressed genes. The deubiquitinating enzyme USP9X was selected, and the inhibitory and targeting effects of chicoric acid on USP9X were subsequently determined. In vivo and in vitro, DSS-induced colitis was treated with USP9X inhibitors WP1130 and EOAI3402143. Ubiquitination label-free quantitative proteomic analysis was performed to identify protein peptides that may undergo de-ubiquitination by USP9X. Co-immunoprecipitation (Co-IP), immunohistochemistry and western blotting were used to validate in vivo and in vitro results.
Chicoric acid significantly alleviated clinical activity and histological changes, inhibited pro-inflammatory cytokine production and improved integrity of the intestinal barrier in UC mice. Moreover, chicoric acid suppressed USP9X expression in colonic tissues from UC mice. Furthermore, USP9X contributed to promoting the onset of UC and that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was deubiquitinated by USP9X.
Chicoric acid ameliorated DSS-induced colitis by targeting the USP9X/IGF2BP2 axis, indicating that targeting the USP9X/IGF2BP2 axis presents a promising and innovative therapeutic approach for the treatment of UC.
This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc.
菊苣酸是一种羟基肉桂酸，具有抗炎活性。然而，菊苣酸对葡聚糖硫酸钠（DSS）诱导的结肠炎作用的具体机制尚不清楚。在此，我们旨在阐明菊苣酸对DSS诱导的结肠炎保护作用的分子机制。
用菊苣酸对DSS诱导的结肠炎小鼠（UC小鼠）进行为期一周的治疗。评估结肠炎症状、结肠病理学、炎症相关指标和肠黏膜屏障功能。对结肠组织进行RNA测序以获得差异表达基因。选择去泛素化酶USP9X，随后确定菊苣酸对USP9X的抑制和靶向作用。在体内和体外，用USP9X抑制剂WP1130和EOAI3402143治疗DSS诱导的结肠炎。进行无泛素化标记定量蛋白质组分析以鉴定可能被USP9X去泛素化的蛋白质肽段。采用免疫共沉淀（Co-IP）、免疫组织化学和蛋白质印迹法验证体内和体外实验结果。
菊苣酸显著减轻UC小鼠的临床活动度和组织学变化，抑制促炎细胞因子产生并改善肠屏障完整性。此外，菊苣酸抑制UC小鼠结肠组织中USP9X的表达。此外，USP9X促进UC发病，胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）被USP9X去泛素化。
菊苣酸通过靶向USP9X/IGF2BP2轴改善DSS诱导的结肠炎，表明靶向USP9X/IGF2BP2轴为UC治疗提供了一种有前景的创新治疗方法。
本文是主题为“代谢和慢性炎症性疾病中的药物和药物靶点”特刊的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc。
