Background The anti-tumor properties of curcumin have been elucidated in many cancer types. However, a systematic functional and biological analysis related to its target proteins has yet to be documented fully. The aim of this study was to explore the underlying mechanisms of curcumin and broaden the perspective of targeted therapies. Methods Direct protein targets (DPTs) of curcumin were searched in the DrugBank database. Using the STRING database, the interaction between curcumin and DPTs and indirect protein targets (IPTs) was documented. The protein–protein interaction (PPI) network of curcumin-mediated proteins was visualized using Cytoscape. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed for all curcumin-mediated proteins. Furthermore, the cancer targets were searched in the Comparative Toxicogenomics Database (CTD). The overlapping targets were studied using Kaplan–Meier analysis to evaluate cancer survival. Further genomic analysis of overlapping genes was conducted using the cBioPortal database. Lastly, CKK-8, qPCR, and WB analysis were used to validate the predicted results on HCC cells. Results A total of 5 DPTs and 199 IPTs were found. These protein targets were found in 121 molecular pathways analyzed via KEGG enrichment. Based on the anti-tumor properties of curcumin, two pathways were selected, including pathways in cancer (36 genes) and hepatocellular carcinoma (HCC) pathway (22 genes). Overlapping with 505 HCC-related gene sets identified in CTD, five genes (TP53、 RB1、 TGFB1、 GSTP1、 and GSTM1) were finally identified. High mRNA levels of TP53, RB1, and GSTM1 indicated a prolonged OS in HCC, while elevated mRNA levels of TGFB1 were correlated with poor prognosis. The viability of HepG2 cells and Hep3B cells can both be significantly reduced by curcumin at concentrations of 20 or 30 µM after 48 or 72 h of culture. At a concentration of 20 µM curcumin, the expression of TGFB1 and GSTP1 in Hep3B cells was reduced significantly in qPCR analysis, and reduced TGFB1 protein expression was also found in Hep3B cells. Conclusions The current results provided evidence that curcumin has the potential to become an alternative chemotherapy or chemoprevention for HCC.
