Disrupting the BEX4-Mediated DNA Repair Rheostat with a Novel Inhibitor Suppresses Stemness and Enhances Chemosensitivity in Hepatoblastoma.

Authors

Zeyu Yan, Qian Wang, Jing Li, Hui Zhang, Mengmeng Feng, Renyu Zhang, Dan Wu, Zifeng Zhao, Zhang Zhang, Dalin Wang, Hongxin Zhang, Hongchen Zhang, Chongzhi Hou, Xianli He, Tao Yang

Published in

Pharmacological research. Pages 109658. Sep 30, 2026. Epub Sep 30, 2026.

Abstract

Cisplatin resistance in hepatoblastoma (HB) is a major therapeutic barrier. Emerging evidence suggests that cancer cells can activate DNA double-strand break repair pathways to evade chemotherapy-induced apoptosis and sustain stemness; however, the mechanisms underlying cisplatin resistance in HB remain poorly understood. Here, we identified the neuronal protein BEX4 as a key mediator of cisplatin resistance. BEX4 was aberrantly overexpressed in HB cells and maintained a stem-like state. Mechanistically, BEX4 bound to and stabilized the core nonhomologous end-joining (NHEJ) factor X-ray repair cross-complementing protein 5 (XRCC5), thereby promoting NHEJ activity and contributing to cisplatin resistance. DNA damage induced ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of BEX4 at Thr107, promoting transient dissociation of the BEX4-XRCC5 complex and facilitating XRCC5 recruitment to DNA damage sites. BEX4-driven NHEJ enhances DNA damage repair, thereby promoting genomic instability, stemness, and chemoresistance. Building on these mechanistic findings, we identified a small-molecule compound, F35-303, which disrupted the BEX4-XRCC5 interaction, suppressed NHEJ activity, and restored cisplatin sensitivity in resistant preclinical models. Our findings identify BEX4 as a key mediator of cisplatin resistance in HB and suggest that targeting the BEX4-XRCC5 interaction with F35-303 may provide a new therapeutic strategy for overcoming chemoresistance in HB and a mechanistic framework for understanding adaptive chemoresistance.

PMID:
42815815
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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