Role of cell cycle-related gene as a potential target of nitidine chloride in hepatocellular carcinoma progression.

Background: Hepatocellular carcinoma (HCC) is at the forefront of the global spectrum of cancer incidence and mortality, with conventional therapies like tyrosine kinase inhibitors limited by resistance. Recent studies have highlighted the promising anticancer effects of nitidine chloride (NC) against HCC. SAC3 domain containing 1 (SAC3D1) is critical for centrosome replication and spindle formation. However, research on SAC3D1 in HCC and NC remains limited.

Aim: To investigate the mechanisms underlying SAC3D1's role in HCC progression and evaluated its potential as a therapeutic target of NC.

Methods: RNA sequencing (RNA-seq) identified SAC3D1 expression changes in HCC cells after NC treatment. Molecular docking was further employed to validate the direct binding between NC and SAC3D1. Additionally, HCC multicenter data (The Cancer Genome Atlas_GTEx, ArrayExpress), pathway analysis, Pearson correlation analysis and SAC3D1 knockdown experiments were integrated to explore the molecular mechanisms underlying SAC3D1's involvement in HCC progression.

Results: RNA-seq showed that NC treatment significantly downregulated SAC3D1 expression [log(fold change) = - 0.95, < 0.05], with molecular docking revealing that NC directly bound to SAC3D1 proteins (binding energy: -9.7 kcal/mol). Enrichment analysis showed that most pathways were closely related to the cell cycle. Pearson correlation analysis indicated that SAC3D1 and cell cycle genes were significantly positively correlated(correlation coefficient ≥ 0.3, < 0.05). SAC3D1 knockdown inhibited HCC cell invasion, migration, and proliferation by arresting cells in the S and G2/M phases. Flow cytometry confirmed that after SAC3D1 knockdown, the early and total apoptosis percentage of HCC cells decreased, while the late apoptosis percentage increased.

Conclusion: As a potential target of NC, SAC3D1 may inhibit HCC progression through cell cycle regulation following its downregulation by NC.