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REVIEW

Targeting PCNA in Cancer: A Paradigm Shift from Static Inhibition to Dynamic Network Modulation

Shijia Lu1,#, Yanmin Wang1,#, Han Zhang1, Mengjia Yan1, Mengdan Sang2, Jinle Wang1, Huaying Du3, Jinwen Sima3, Yiran Zhen2, Xue Yang2, Yutong Zhang1, Hongwei Zhou1,*
1 School of Life Science and Technology, North Henan Medical University, Xinxiang, China
2 School of Medical Laboratory, North Henan Medical University, Xinxiang, China
3 Basic Medical College, North Henan Medical University, Xinxiang, China
* Corresponding Author: Hongwei Zhou. Email: email
# These authors are co-first authors of the article

Oncology Research https://doi.org/10.32604/or.2026.079988

Received 01 February 2026; Accepted 15 April 2026; Published online 11 May 2026

Abstract

Proliferating Cell Nuclear Antigen (PCNA) is a core protein in DNA replication and repair. Its functional dysregulation drives tumorigenesis and therapeutic resistance, making it a critical anticancer target. However, the fundamental conflict between PCNA’s indispensable “guardian” function in normal cells and its hijacked “accomplice” role in cancer cells constitutes the central challenge for targeted intervention: how to eradicate tumors while avoiding severe toxicity to normal tissues. This review aims to systematically review the latest advances and translational dilemmas in the field of PCNA-targeted therapy. It outlines various intervention strategies, including small-molecule inhibitors, proteolysis-targeting chimeras, post-translational modification interference, and synthetic lethality approaches, analyzing their potential and limitations in preclinical research. The review focuses on dissecting key bottlenecks hindering clinical translation, such as the selectivity dilemma, delivery barriers, and resistance evolution. Concurrently, it critically examines how cross-disciplinary technologies—including artificial intelligence, spatiotemporal regulation, and synthetic biology—offer novel ideas to address these bottlenecks, while clarifying that most remain in early exploratory stages. By synthesizing progress, challenges, and future directions, this article provides a framework to inform the development of highly selective and translatable PCNA-based anticancer strategies.

Graphical Abstract

Targeting PCNA in Cancer: A Paradigm Shift from Static Inhibition to Dynamic Network Modulation

Keywords

Proliferating cell nuclear antigen; targeted protein degradation; artificial intelligence; precision therapy; tumor microenvironment; synthetic lethality; clinical translation

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