A Natural PCID2-Targeting Compound Suppresses Hepatocellular Carcinoma Progression: Evidence from Structure-Based Discovery and Biological Evaluation

Zebanuer Yuemaierjiang¹Jingjing Sun^1,2Jiaming Song¹Jiaping Huang¹Huiyu Zhang¹Lili Xi^1,3*Jingjing Guo^4*Xinyi Luo⁵

• ¹The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
• ²Medical Laboratory Center, The First Hospital of Lanzhou University, Lanzhou, China
• ³Office of Institution of Drug Clinical Trial, The First Hospital of Lanzhou University, Lanzhou, China
• ⁴Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Science, Macao Polytechnic University, Macao, China
• ⁵Department of pharmacy, the first hospital of lanzhou university, Lanzhou, China

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis, highlighting the urgent need for novel targets and effective agents. PCID2 (PCI-domain containing protein 2) has recently been recognized as a potential therapeutic target; however, specific inhibitors remain unidentified. In this study, we explored natural product-based small molecular targeting PCID2, with a particular focus on monomeric compounds derived from traditional Chinese medicine (TCM). Using a molecular docking-based virtual screening strategy, 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (β-PGG) was identified as a promising candidate, and its binding affinity to PCID2 was subsequently confirmed by SPR analysis. The cytotoxicity of β-PGG and its effects on malignant phenotypes of HCC cells were evaluated in vitro, and functional assays demonstrated that β-PGG treatment markedly inhibited the proliferation, migration and invasion in HCC cells, which simultaneously promoting apoptosis and inducing cell cycle arrest, thereby blocking the transition from G0/G1 or S phase to G2/M phase. Mechanistically, Western blot analysis revealed that β-PGG significantly reduced PCID2 expression, accompanied by decreased levels of cell cycle regulators Cyclin D1 and CDK6. Notably, high concentrations of β-PGG also suppressed the phosphorylation of PI3K and Akt. In conclusion, these findings suggest that β-PGG is a promising natural compound with PCID2-targeting potential. By modulating PCID2 expression, This is a provisional file, not the final typeset article PI3K/Akt signaling, and key cell cycle regulators, β-PGG exerts potent anti-HCC effects. This study not only support a rationale for further exploration of PCID2 as a therapeutic target in HCC but also provide valuable insights into the discovery of novel lead compounds from TCM for liver cancer treatment.