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

doi:10.3969/j.issn.1674-8115.2026.08.004

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (8): 1026-1036.doi: 10.3969/j.issn.1674-8115.2026.08.004

• 论著 · 基础研究 • 上一篇

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

翟元晖¹, 王莹莹¹, 王宇轩², 吴文萱¹, 朱楚娇¹, 张幼萍¹, 白雯会¹, 雷虎¹, 徐含章¹, 赵亚雪²(), 吴英理¹()

^1.上海交通大学医学院附属同仁医院虹桥国际医学研究院/基础医学院，上海市高校E-研究院化学生物学分部，细胞分化与凋亡教育部重点实验室，上海 201318
^2.上海交通大学药学院，上海 200240

收稿日期:2026-03-03 接受日期:2026-03-27 出版日期:2026-08-28 发布日期:2026-08-28
通讯作者: 吴英理，教授，博士；电子信箱：wuyingli@shsmu.edu.cn
赵亚雪，副研究员，博士；电子信箱：yaxuezhao@sjtu.edu.cn。
作者简介:第一联系人：翟元晖、吴文萱、朱楚娇、张幼萍、白雯会负责实验操作，王宇轩、赵亚雪负责蛋白结构预测，翟元晖负责论文撰写，翟元晖、王莹莹、吴英理参与研究设计，雷虎、徐含章对论文进行了修改。所有作者均阅读并同意了最终稿件的提交。
为共同第一作者（co-first authors)。
基金资助:
国家自然科学基金(82470152);国家自然科学基金(82400092);国家自然科学基金(82170145);国家自然科学基金(82170172);中国博士后科学基金(2024M762019)

Research on the effects and mechanisms of bardoxolone methyl as a novel inhibitor of ubiquitin-specific protease 48 in inhibiting colorectal cancer

Zhai Yuanhui¹, Wang Yingying¹, Wang Yuxuan², Wu Wenxuan¹, Zhu Chujiao¹, Zhang Youping¹, Bai Wenhui¹, Lei Hu¹, Xu Hanzhang¹, Zhao Yaxue²(), Wu Yingli¹()

^1.Hongqiao International Institute of Medicine/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201318, China
^2.School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

Received:2026-03-03 Accepted:2026-03-27 Online:2026-08-28 Published:2026-08-28
Contact: Wu Yingli, E-mail: wuyingli@shsmu.edu.cn
Zhao Yaxue, E-mail: yaxuezhao@sjtu.edu.cn.
About author:First author contact:Zhai Yuanhui, Wu Wenxuan, Zhu Chujiao, Zhang Youping, and Bai Wenhui performed the experiments. Wang Yuxuan and Zhao Yaxue were responsible for protein structure prediction. The manuscript was prepared by Zhai Yuanhui. Zhai Yuanhui, Wang Yingying, and Wu Yingli contributed to the study design. Lei Hu and Xu Hanzhang revised the paper. All authors have read the last version of paper and consented to its submission.
Supported by:
National Natural Science Foundation of China(82470152);China Postdoctoral Science Foundation(2024M762019)

摘要/Abstract

摘要：

目的·探讨甲基巴多索隆（bardoxolone methyl，CDDO-Me）对泛素特异性蛋白酶48（ubiquitin-specific protease 48，USP48）的抑制作用及其抗结直肠癌机制。方法·采用体外酶活性测定、热位移分析（thermal shift assay，TSA）及分子对接技术，验证CDDO-Me与USP48的结合能力及对其酶活性的抑制作用。通过细胞热位移实验（cellular thermal shift assay，CETSA）验证CDDO-Me在结直肠癌细胞中与USP48的靶向结合。利用蛋白质印迹法（Western blotting）检测CDDO-Me对USP48底物高迁移率族蛋白A2（high mobility group AT-hook 2，HMGA2）、活化B细胞的核因子κB p65亚基（nuclear factor NF-κB p65 subunit，RelA/p65）表达及泛素化修饰的影响。采用划痕愈合实验、细胞计数试剂盒-8（cell counting kit-8，CCK-8）实验，检测CDDO-Me对结直肠癌细胞迁移及增殖活力的作用，并通过USP48过表达实验验证其靶向性。建立小鼠MC38结直肠癌皮下移植瘤模型及肺转移模型，探究CDDO-Me的体内抗肿瘤作用。通过免疫组织化学检测肿瘤组织中细胞增殖核抗原Ki-67、脱氧核糖核苷酸末端转移酶介导的缺口末端标记（terminal-deoxynucleotidyl transferase mediated nick end labeling，TUNEL）指标、HMGA2、p65的表达。结果·CDDO-Me在体外能够直接结合USP48，并显著抑制其去泛素化酶活性。CETSA实验证实，CDDO-Me可在结直肠癌细胞中与USP48特异性结合。CDDO-Me通过抑制USP48，增强了HMGA2的K48位连接泛素化修饰，促进其经蛋白酶体降解，呈剂量依赖性地下调结直肠癌细胞中HMGA2、p65的蛋白表达。CDDO-Me显著抑制结直肠癌细胞的迁移和增殖活力，而USP48过表达可逆转上述作用。体内实验表明，CDDO-Me显著抑制小鼠MC38结直肠癌皮下移植瘤的生长及肺转移，降低肿瘤组织中Ki-67、HMGA2、p65的表达，增加TUNEL阳性细胞数。结论·CDDO-Me是一种新型的USP48抑制剂，可通过靶向抑制USP48，促进致癌底物HMGA2的泛素化降解，进而抑制结直肠癌细胞的增殖、迁移及体内肿瘤的生长和转移。

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

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.

Key words: bardoxolone methyl (CDDO-Me), ubiquitin-specific protease 48 (USP48), inhibitor, deubiquitinating enzyme, colorectal cancer

中图分类号:

R735.3⁺4

翟元晖, 王莹莹, 王宇轩, 吴文萱, 朱楚娇, 张幼萍, 白雯会, 雷虎, 徐含章, 赵亚雪, 吴英理. 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.

Zhai Yuanhui, Wang Yingying, Wang Yuxuan, Wu Wenxuan, Zhu Chujiao, Zhang Youping, Bai Wenhui, Lei Hu, Xu Hanzhang, Zhao Yaxue, Wu Yingli. Research on the effects and mechanisms of bardoxolone methyl as a novel inhibitor of ubiquitin-specific protease 48 in inhibiting colorectal cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026,(8): 1026-1036.

图/表 6

图1 CDDO-Me对USP48体外去泛素化酶活性的抑制作用Note： A. In the gel-based in vitro USP48 activity assay, various compounds (left and right panels) were pre-incubated with USP48 before adding GST-Ub-A52. All compounds were tested at a final concentration of 50 μmol·L-1. B/C. Dose-response relationships of NGA (B) and CDDO-Me (C): after incubating USP48 with gradient concentrations of NGA and CDDO-Me, its activity was quantified using the GST assay. D. IC₅₀ values of NGA and CDDO-Me.

Fig 1 Inhibitory effect of CDDO-Me on the deubiquitinating enzyme activity of USP48 in vitro

图2 CDDO-Me与USP48结合的TSA检测及分子对接分析Note： A. Chemical structure of CDDO-Me. B. TSA results showed the interaction between purified Flag-USP48 protein and 50 μmol·L-1 CDDO-Me (D‒DMSO group; C‒CDDO-Me group). C. Molecular docking revealed the binding mode of CDDO-Me to USP48: hydrogen bonds are indicated by yellow dashed lines, and CDDO-Me interacted with surrounding amino acid residues ( K308, Y354) via hydrogen bonding and hydrophobic interactions.

Fig 2 TSA detection and molecular docking analysis of CDDO-Me binding to USP48

图3 基于CETSA的CDDO-Me与结直肠癌细胞中USP48结合检测Note： A‒C. CETSA was performed in MC38 (A), HCT116 (B), and RKO (C) cells. CETSA results showing the temperature-dependent interaction between USP48 and CDDO-Me (50.00 μmol·L-1). D‒F. CETSA results showing the dose-dependent interaction between USP48 and CDDO-Me at 54.5 ℃ in MC38 (D), HCT116 (E), and RKO (F) cells.

Fig 3 Detection of CDDO-Me binding to USP48 in colorectal cancer cells by CETSA

图4 CDDO-Me通过USP48影响HMGA2稳定性的作用研究Note： A‒C. Vinculin-normalized p65 protein expression in RKO (A), HCT116 (B), and MC38 (C) cells with gradient-concentration CDDO-Me treatment for 5, 24, and 48 h. D‒F β-tubulin-normalized HMGA2 protein expression in RKO (D), HCT116 (E), and MC38 (F) cells with gradient-concentration CDDO-Me treatment for 5, 24, and 48 h. G. Western blotting-detected p65 and vinculin protein levels in RKO cells with CDDO-Me pretreatment and subsequent MG132 incubation. H. Western blotting-detected HMGA2 and β-tubulin protein levels in RKO cells with CDDO-Me pretreatment and subsequent MG132 incubation. I. Relative HMGA2 protein expression for protein half-life analysis under CHX treatment at sequential cell sampling time points. J. Anti-Flag immunoprecipitation was performed to detect HMGA2 ubiquitination. HEK-293T cells were divided into four transfection groups: Flag-HMGA2 single transfection, HA-Ub plus Flag-HMGA2 co-transfection, GFP-USP48 plus HA-Ub plus Flag-HMGA2 co-transfection, and the triple-transfection group with CDDO-Me treatment.

Fig 4 Analysis of the mechanism by which CDDO-Me regulates the stability of the HMGA2 protein through USP48

图5 CDDO-Me对结直肠癌细胞增殖及迁移能力的影响Note： A. USP48 overexpression efficiency assessed by Western blotting analysis of GFP-tagged constructs in HCT116 cells. B. β-tubulin-normalized HMGA2 protein levels in USP48-overexpressing HCT116 cells after 24 h exposure to gradient CDDO-Me concentrations. C. Wound closure analysis of MC38 cells treated with DMSO and CDDO-Me. D. Quantification of wound closure in parental and USP48-expressing HCT116 cells treated with DMSO and CDDO-Me. E. USP48 overexpression efficiency assessed by Western blotting analysis of GFP-tagged constructs in RKO cells. F/G. Cell viability of parental and USP48‑expressing RKO (F) and HCT116 (G) cells treated with CDDO‑Me, as assessed by the CCK-8 assay.

Fig 5 Effects of CDDO-Me on the proliferation and migration of colorectal cancer cells

图6 CDDO-Me在体内对结直肠癌生长及肺转移的影响Note： A‒C. Representative images (A) of excised MC38 tumors, tumor volume quantification (B), and serial monitoring of animal body weight (C). D. HE, Ki-67, TUNEL, p65, and HMGA2 staining of tumor sections from vehicle- and CDDO-Me-treated groups (×40). E. HE staining of lung sections from vehicle- and CDDO-Me-treated groups (×40).

Fig 6 Effects of CDDO-Me on the growth and lung metastasis of colorectal cancer in vivo

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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

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