Yang HW, Chen X, Wu WJ, Yang L, Fang XB. GINS complex couples DNA replication stress to therapeutic resistance in hepatocellular carcinoma. World J Gastrointest Oncol 2026; 18(11): 124074 [DOI: 10.4251/wjgo.124074]
Corresponding Author of This Article
Xing-Bao Fang, MD, Chief, Chief Physician, Professor, Department of Hepatobiliary and Pancreatic Surgery, Qujing Central Hospital of Yunnan Province, No. 1 Yuanlin Road, Qujing 655000, Yunnan Province, China. fangxingbao@kmmu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
review-article
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastrointest Oncol. Nov 15, 2026; 18(11): 124074 Published online Nov 15, 2026. doi: 10.4251/wjgo.124074
GINS complex couples DNA replication stress to therapeutic resistance in hepatocellular carcinoma
Hao-Wen Yang, Xi Chen, Wen-Jie Wu, Liu Yang, Xing-Bao Fang
Hao-Wen Yang, Wen-Jie Wu, Liu Yang, Affiliated Qujing Hospital, Kunming Medical University, Kunming 650000, Yunnan Province, China
Xi Chen, Xing-Bao Fang, Department of Hepatobiliary and Pancreatic Surgery, Qujing Central Hospital of Yunnan Province, Qujing 655000, Yunnan Province, China
Author contributions: Chen X, Wu WJ, and Yang L contributed to writing, review & editing; Yang HW contributed to conceptualization, writing of original draft, and visualization (figures and tables); Chen X contributed to literature search and data curation; Wu WJ contributed to formal analysis and validation; Yang L contributed to investigation and methodology; Fang XB contributed to supervision, funding acquisition, project administration, and final approval of the manuscript. All authors have read and agreed to the published version of the manuscript.
AI contribution statement: All contents of this manuscript, including AI-assisted text, are the sole responsibility of all authors. All AI outputs were thoroughly checked and approved by authors. AI tools were not applied to generate raw data, perform data analysis or derive research conclusions.
Supported by the Science Research Fund Project of Yunnan Provincial Department of Education, No. 2026Y0383; and the Xingdian Talent Support Program.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Xing-Bao Fang, MD, Chief, Chief Physician, Professor, Department of Hepatobiliary and Pancreatic Surgery, Qujing Central Hospital of Yunnan Province, No. 1 Yuanlin Road, Qujing 655000, Yunnan Province, China. fangxingbao@kmmu.edu.cn
Received: June 5, 2026 Revised: June 30, 2026 Accepted: August 26, 2026 Published online: November 15, 2026 Processing time: 142 Days and 4.8 Hours
Abstract
DNA replication stress is a central molecular event in tumorigenesis and cancer progression. As an essential component of the eukaryotic replisome, the GINS complex, composed of GINS1/PSF1, GINS2/PSF2, GINS3/PSF3, and GINS4/SLD5, cooperates with CDC45 and MCM2-7 to form the Cdc45-MCM-GINS helicase, which drives replication initiation and fork elongation. Aberrant expression of GINS subunits has been linked to cell-cycle activation, genomic instability, epithelial-mesenchymal transition, cancer stemness, immune microenvironment remodeling, and therapeutic resistance. Hepatocellular carcinoma (HCC) remains a major global health burden, with approximately 685000 new cases and 597000 deaths worldwide in 2022, and resistance to immune checkpoint inhibitor-based combinations, dual immunotherapy, and multitarget tyrosine kinase inhibitors continues to limit durable clinical benefit. This minireview summarizes the biological roles of the GINS complex and DNA replication stress in tumor progression, stemness, and therapeutic resistance, with a focus on their translational relevance in HCC. Current HCC evidence mainly implicates GINS1, GINS2, and GINS4, including the emerging GINS4/POLE2/ferroptosis axis, whereas GINS3 remains insufficiently validated. Therefore, the GINS-CMG axis should be regarded as a candidate biomarker and hypothesis-generating therapeutic concept rather than an established causal driver in HCC.
Core Tip: This review highlights the GINS complex, a core component of the CMG helicase, as a candidate molecular link between DNA replication stress adaptation, cancer stemness, epithelial-mesenchymal transition, and therapeutic resistance in hepatocellular carcinoma (HCC). Current evidence is strongest for GINS1, GINS2, and GINS4, whereas HCC-specific functional validation of GINS3 remains limited. The GINS-CMG axis should therefore be viewed as a hypothesis-generating biomarker and translational concept rather than an established therapeutic target.
