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World J Gastrointest Oncol. Sep 15, 2026; 18(9): 120170
Published online Sep 15, 2026. doi: 10.4251/wjgo.120170
IQGAP1 promotes tumor progression by stabilizing MCM3/Nrf2 in cholangiocarcinoma
Zhi-Yuan Ren, Hong-Yan Zhang, Chen-Xi Xie, Geng-Ping Zhou, Peng-Yu Chen, Hao Yuan, Kai Zhang, Yang Xu, Yang-Yang Wang, Tai-Yang Chen, Qing-Shan Li, Hai-Bo Yu
Zhi-Yuan Ren, Hong-Yan Zhang, Chen-Xi Xie, Geng-Ping Zhou, Peng-Yu Chen, Hao Yuan, Kai Zhang, Yang Xu, Yang-Yang Wang, Tai-Yang Chen, Hepatobiliary Center, Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
Qing-Shan Li, National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Hai-Bo Yu, Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
Co-first authors: Zhi-Yuan Ren and Hong-Yan Zhang.
Co-corresponding authors: Qing-Shan Li and Hai-Bo Yu.
Author contributions: Ren ZY and Zhang HY contribute equally to this study as co-first authors; Li QS and Yu HB contribute equally to this study as co-corresponding authors; Yu HB and Li QS completed conception and design; Ren ZY, Xie CX and Zhou GP completed development of methodology; Zhang HY, Chen PY, Yuan H and Zhang K completed collection and acquisition of data; Xu Y, Wang YY and Chen TY completed analysis of data; Yu HB, Li QS, Ren ZY and Xie CX completed writing, review, and/or revision of the manuscript; and all the authors have read and approved the final manuscript.
Supported by Henan Young and Middle-Aged Health Science and Technology Innovation Leading Talents Training Project, No. YXKC2022002.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Ethical and Welfare Committee of Guangzhou Yongnuo Medical Experimental Animal Center (Approval No. IACUC-AEWC-F250801002).
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The original contributions presented in the study are included in the article and Supplementary material, and further inquiries can be directed to the corresponding authors.
Corresponding author: Hai-Bo Yu, PhD, Professor, Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou 450003, Henan Province, China.
yhb2101661@zzu.edu.cn
Received: February 24, 2026
Revised: April 6, 2026
Accepted: May 7, 2026
Published online: September 15, 2026
Processing time: 189 Days and 22.8 Hours
BACKGROUND
IQGAP1 has been identified as a key regulator of tumor progression in multiple malignancies, although its specific role and molecular mechanism in cholangiocarcinoma (CCA), the second most common primary hepatobiliary malignancy, remain largely uncharacterized. The Nrf2/KEAP1 pathway is the core axis regulating cellular oxidative stress, which is closely associated with CCA development and therapeutic resistance.
AIM
To define the oncogenic role and mechanism of IQGAP1 in CCA.
METHODS
We screened differentially expressed genes in CCA via bioinformatic analysis of four public datasets (The Cancer Genome Atlas, GSE107943, GSE26566, GSE76297). A series of in vitro functional assays were performed to evaluate IQGAP1’s biological function in CCA cells. Co-IP-MS, molecular docking, ubiquitination assays and Western blot explored underlying molecular mechanisms. In vivo nude mouse xenograft models validated the oncogenic role of IQGAP1/MCM3/Nrf2 axis.
RESULTS
IQGAP1 was significantly upregulated in CCA tissues and cell lines, and its high expression promoted the proliferation, migration, and anti-apoptotic ability of CCA cells in vitro, as well as tumor growth in vivo. Mechanistically, IQGAP1 recruited the deubiquitinase ubiquitin-specific peptidase 28 to directly interact with MCM3, reducing K48-linked ubiquitination and degradation of MCM3 protein, thereby stabilizing MCM3 expression. Upregulated MCM3 competitively bound to KEAP1, blocking the interaction between KEAP1 and Nrf2, which in turn inhibited Nrf2 ubiquitination, activated the Nrf2 antioxidant pathway, alleviated intracellular oxidative stress, and suppressed CCA cell apoptosis. Rescue experiments confirmed that MCM3 knockdown completely reversed the oncogenic phenotypes induced by IQGAP1 overexpression.
CONCLUSION
We first demonstrate IQGAP1 drives CCA progression via post-translationally stabilizing MCM3/Nrf2 axis, serving as a promising prognostic biomarker and therapeutic target with novel mechanistic insights into CCA pathogenesis.
Core Tip: This study reveals for the first time that IQGAP1 drives cholangiocarcinoma progression by recruiting ubiquitin-specific peptidase 28 to stabilize MCM3 protein, inhibiting its ubiquitination. This stabilization activates the Nrf2 pathway, alleviating oxidative stress and suppressing apoptosis, thereby promoting tumor cell survival and growth. Inhibition of MCM3 reverses these effects. The findings identify IQGAP1 as a key regulator of the MCM3/Nrf2 axis and a promising therapeutic target.
