Glypican-3 (GPC3) is a membrane-associated glycoprotein that is significantly upregulated in hepatocellular carcinomas (HCC) but not in normal tissues, making it a promising target for targeted radiopharmaceutical therapy. The study introduces DOTA-RYZ-GPC3 (RAYZ-8009), a novel macrocyclic peptide binder to GPC3, which can be complexed with different radioisotopes. RAYZ-8009 showed high binding affinity to GPC3 in human, mouse, canine, and cynomolgus monkey origins and no binding to other glypican family members. Radiometric studies confirmed potent cellular binding and efficient internalization in GPC3-positive HepG2 cells. In vivo biodistribution studies using 177Lu-RAYZ-8009 demonstrated sustained tumor uptake and fast renal clearance, with minimal or no uptake in normal tissues. Tumor-specific uptake was also observed in orthotopic HCC tumors. Therapeutically, 177Lu- and 225Ac-labeled RAYZ-8009 achieved significant and durable tumor regression and survival benefits in GPC3-positive HCC xenografts, both as single agents and in combination with lenvatinib. Preclinical data support the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3-positive HCC.Glypican-3 (GPC3) is a membrane-associated glycoprotein that is significantly upregulated in hepatocellular carcinomas (HCC) but not in normal tissues, making it a promising target for targeted radiopharmaceutical therapy. The study introduces DOTA-RYZ-GPC3 (RAYZ-8009), a novel macrocyclic peptide binder to GPC3, which can be complexed with different radioisotopes. RAYZ-8009 showed high binding affinity to GPC3 in human, mouse, canine, and cynomolgus monkey origins and no binding to other glypican family members. Radiometric studies confirmed potent cellular binding and efficient internalization in GPC3-positive HepG2 cells. In vivo biodistribution studies using 177Lu-RAYZ-8009 demonstrated sustained tumor uptake and fast renal clearance, with minimal or no uptake in normal tissues. Tumor-specific uptake was also observed in orthotopic HCC tumors. Therapeutically, 177Lu- and 225Ac-labeled RAYZ-8009 achieved significant and durable tumor regression and survival benefits in GPC3-positive HCC xenografts, both as single agents and in combination with lenvatinib. Preclinical data support the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3-positive HCC.