上海交通大学学报（医学版）2026，Vol.46Issue(8)：1026-1036,11.DOI:10.3969/j.issn.1674-8115.2026.08.004
甲基巴多索隆作为新型泛素特异性蛋白酶48抑制剂抑制结直肠癌的作用及机制研究
Research on the effects and mechanisms of bardoxolone methyl as a novel inhibitor of ubiquitin-specific protease 48 in inhibiting colorectal cancer
摘要
Abstract
Objective·To explore the inhibitory effect of bardoxolone methyl(CDDO-Me)on ubiquitin-specific protease 48(USP48)and its mechanisms against colorectal cancer.Methods·In vitro enzyme activity assays,thermal shift analysis(TSA),and molecular docking techniques were employed to verify the binding ability of CDDO-Me to USP48 and its inhibitory effect on USP48 enzymatic activity.The cellular thermal shift assay(CETSA)was used to confirm the targeted binding of CDDO-Me to USP48 in colorectal cancer cells.Western blotting was utilized to detect the impact of CDDO-Me on the expression levels and ubiquitination modifications of the USP48 substrates high mobility group AT-hook 2(HMGA2)and nuclear factor NF-κB p65 subunit(RelA/p65).Wound-healing assay and cell counting kit-8(CCK-8)assay were adopted to examine the effects of CDDO-Me on the migration and proliferative activities of colorectal cancer cells,and the USP48 overexpression experiments were carried out to verify its target specificity.Subcutaneous xenograft and lung metastasis models of MC38 colorectal cancer were established in mice to investigate the in vivo anti-tumor effects of CDDO-Me,and immunohistochemistry was used to detect the expression levels of cell proliferation nuclear antigen Ki-67,terminal-deoxynucleotidyl transferase-mediated nick end labeling(TUNEL),HMGA2,and p65 in tumor tissues.Results·CDDO-Me directly bound to USP48 in vitro and significantly inhibited its deubiquitinating activity.CETSA experiment confirmed that CDDO-Me specifically interacted with USP48 in colorectal cancer cells.By inhibiting USP48,CDDO-Me enhanced K48-linked ubiquitination of HMGA2,promoted its proteasomal degradation,and down-regulated the protein expression levels of HMGA2 and p65 in colorectal cancer cells in a dose-dependent manner.CDDO-Me significantly inhibited the migration and proliferative activities of colorectal cancer cells,and USP48 overexpression reversed these effects.In vivo experiments indicated that CDDO-Me significantly inhibited the growth and lung metastasis of MC38 colorectal cancer subcutaneous xenografts in mice,decreased the expression levels of Ki-67,HMGA2,and p65 in tumor tissues,and increased the number of TUNEL-positive cells.Conclusion·CDDO-Me is a novel USP48 inhibitor.It can promote the ubiquitination-mediated degradation of the oncogenic substrate HMGA2 by targeting and inhibiting USP48,thereby suppressing the proliferation and migration of colorectal cancer cells,as well as tumor growth and metastasis in vivo.关键词
甲基巴多索隆/泛素特异性蛋白酶48/抑制剂/去泛素化酶/结直肠癌Key words
bardoxolone methyl(CDDO-Me)/ubiquitin-specific protease 48(USP48)/inhibitor/deubiquitinating enzyme/colorectal cancer分类
医药卫生引用本文复制引用
翟元晖,赵亚雪,吴英理,王莹莹,王宇轩,吴文萱,朱楚娇,张幼萍,白雯会,雷虎,徐含章..甲基巴多索隆作为新型泛素特异性蛋白酶48抑制剂抑制结直肠癌的作用及机制研究[J].上海交通大学学报（医学版）,2026,46(8):1026-1036,11.基金项目
国家自然科学基金(82470152,82400092,82170145,82170172) （82470152,82400092,82170145,82170172）
中国博士后科学基金(2024M762019). National Natural Science Foundation of China(82470152,82400092,82170145,82170172) （2024M762019）
China Postdoctoral Science Foundation(2024M762019). （2024M762019）
