OBJECTIVE To investigate the molecular mechanism of curcumol on hepatic stellate cell senescence based on network pharmacology and experimental validation.

METHODS Curcumol targets were obtained from Pharm Mapper database; cellular senescence-related targets were collected from GeneCard, OMIM and PharmGKB databases. The key targets were obtained by interacting curcumol targets and cellular senescence-related targets. The key target interaction network was constructed based on the String database and visualized by Cytoscape software. The key targets were enriched for pathways and functions, and molecular docking analysis was performed between the key targets and curcumol. The effect and mechanism of curcumol on hepatic stellate cell senescence was examined by molecular biology experiments.

RESULTS A total of 152 curcumol action targets, 2937 cellular senescence-related targets and 71 key targets of curcumol regulation of cellular senescence were obtained. The enrichment analysis revealed that the key targets were mainly involved in metabolic process, transcription factor activity, antioxidant activity, etc., mainly enriched in IL-17, VEGF, Ras, autophagy, MAPK and other signaling pathways; and the molecular docking results showed that curcumol has better binding ability with the key targets; CCK8 experiment found that curcumol significantly inhibited cell proliferation(P<0.01); molecular biology experiment found that curcumol blocked cell cycle in G0/G1 phase(P<0.05); increased the expression of cellular senescence and autophagy-related proteins(P<0.05); inhibited MAP8 and MAPK14 mRNA and extracellular matrix expression(P<0.01); transmission electron microscopy detected that curcumol significantly increased the number of autophagic vesicles(P<0.01); β-Galactosidase staining assay revealed that curcumol-induced cellular senescence was rescued by 3-MA.

CONCLUSION Curcumol regulates cellular autophagy by targeting MAPK8 and MAPK14, and induces hepatic stellate cell senescence may be one of the key mechanisms of curcumol against liver fibrosis.