Diosmetin inhibits cells growth and proliferation by regulating cell cycle and lipid metabolism pathway in hepatocellular carcinoma

Diosmetin (DSM), a new discovered natural flavonoid, present in citrus plants or olive leaves which were reported to prevent cancer progress as food supplement. This study was to investigate the anti-Hepatocellular carcinoma (HCC) effects and its possible molecular mechanism of DSM. The results showed that DSM decreased the Hep3B and HCCLM3 cells proliferation and migration in a dose dependent manner in vitro. RNA-seq of DSM treatment identified 4459 differentially expressed genes (DEGs), which highly enriched in cell cycle pathway according to the KEGG enrichment analysis. DSM regulated cell growth by arresting cell cycle at G1 phase though decreasing the BCL2, CDK1, CCND1 expression. Metabolomics analysis showed that DSM interfered the liver cancer cell lipid metabolism by significantly inhibiting metabolites acetic acid, decanoic acid, glycerol, L-Proline synthesis. Subcutaneous tumor formation showed that DSM significantly reduced the tumor volume and weight when compared with the control, further immunohistochemical analysis revealed that DSM treatment remarkably decreased the expression of the proliferative marker KI67. Our results demonstrate that DSM exhibits antitumor features against HCC cells via hindering cell proliferation by arresting cell cycle and interfering lipid metabolism.