@Article{or.2026.074144,
AUTHOR = {Kuan-Hao Lin, Yu-Ju Lin, Yu-Bin Hong, Meng-Huai Hsu, Zhen-Xiang Liao, Shuo-Yu Chang, Chiou-Hwa Yuh},
TITLE = {Glutamic Acid–Chelated Cobalt Stabilizes G-Quadruplexes and Selectively Suppresses Hepatocellular Carcinoma Growth},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {4},
PAGES = {--},
URL = {http://www.techscience.com/or/v34n4/66689},
ISSN = {1555-3906},
ABSTRACT = { <b>Objectives:</b> Hepatocellular carcinoma (HCC) has limited systemic options with substantial toxicity. G-quadruplex (G4) structures in oncogene promoters are attractive but challenging drug targets. This study aimed to determine whether glutamic acid–chelated cobalt (GACC) is a G4-active scaffold with anti-HCC efficacy and favorable <i>in vivo</i> safety, and whether an AI-guided phenotypic response surface (PRS) can optimize less toxic combinations. <b>Methods:</b> Anticancer activity was tested in HCC cell lines (PLC/PRF/5, Hep3B, HepG2) and non-transformed THLE-2 hepatocytes (CCK-8, IC<sub>50</sub>). <i>In vivo</i> safety/efficacy were assessed in zebrafish embryo toxicity assays, a Hep3B xenograft model, and a tert-overexpressing transgenic zebrafish model, with hepatotoxicity monitored in a liver-fluorescent reporter line. Target engagement was examined by docking, native PAGE, a KRAS promoter G4 DNA polymerase stop assay, BG4 immunofluorescence, and KRAS qPCR. PRS was used to optimize GACC–metformin–regorafenib combinations. <b>Results:</b> GACC reduced HCC viability (IC<sub>50</sub> ~86–115 µM) and showed low embryotoxicity (IC<sub>50</sub> 6.87 mM). In zebrafish xenografts, GACC (50 µM) reduced Hep3B tumor fluorescence by ~90% without detectable hepatotoxicity, whereas sorafenib decreased liver size/fluorescence. In tert-overexpressing zebrafish, GACC suppressed proliferation and Wnt/β-catenin–associated transcripts and reduced mitotic figures and nuclear atypia. Mechanistically, GACC increased KRAS promoter polymerase stalling, enhanced nuclear G4 signal, and reduced KRAS transcripts. PRS identified an off-grid triple combination that reduced PLC/PRF/5 viability to 19% while maintaining THLE-2 viability at 52% and preserving zebrafish development. <b>Conclusion:</b> GACC is a G4-active cobalt–glutamate scaffold with anti-HCC activity and favorable zebrafish safety, and a zebrafish-plus-PRS workflow enables rational, less toxic combination design.},
DOI = {10.32604/or.2026.074144}
}