Mechanism of GLG1 driving malignant progression of hepatocellular carcinoma and development of targeted compound YHB-5

Background and Purpose: Hepatocellular carcinoma (HCC) poses a significant threat to human life due to its high mortality and recurrence rates. Human Golgi complex Glycoprotein 1 (GLG1) serves as a biomarker for various cancers, but its role in HCC remains unreported. This study aimed to investigate the function and mechanism of GLG1 in the malignant progression of HCC. Experimental Approach: GLG1 expression in HCC was analyzed using clinical databases, qRT-PCR, and Western blot. The potential roles of GLG1 in proliferation, migration, and invasion were determined via CCK-8, colony formation, wound healing, and Transwell assays. Downstream pathways were identified by gene enrichment analysis and Western blot. Potential GLG1-binding compounds were predicted using the DGldb database, leading to the synthesis and optimization of YHB-5, which was tested for its anti-tumor activity. Key Results: Knockdown of GLG1 significantly inhibited the proliferation, migration, and invasion of Huh-7 and MHCC97H cells. Mechanistically, GLG1 was found to exert its oncogenic role by regulating the P53/P21 pathway. Furthermore, the novel small molecule compound YHB-5 demonstrated potent anti-tumor activity against multiple HCC cell lines. Conclusion and Implications: Our findings reveal that GLG1 promotes HCC progression via the GLG1/P53/P21 axis. The newly synthesized GLG1-targeting compound, YHB-5, represents a promising candidate drug, highlighting the potential of GLG1 as a therapeutic target for the diagnosis and treatment of hepatocellular carcinoma.