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.<h4>Conclusion</h4>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. The gene discussed is HSPG2; the disease is hepatocellular carcinoma.