Integrated network pharmacology reveal new key curcumin-binding targets in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive malignancy lacking targeted therapies, leading to limited treatment options. Curcumin, a natural polyphenol from Curcuma longa, exhibits promising anticancer activity, but its precise molecular mechanisms and key targets in TNBC remain largely unclear. This study aimed to clarify curcumin's antitumor mechanisms and identify its key targets in TNBC.

To clarify curcumin's antitumor mechanisms in TNBC, an integrated approach was used, including network pharmacology, molecular docking, 500 ns molecular dynamics simulations, free energy landscape analysis, and MM/PBSA binding free energy calculations.

Network pharmacology analysis identified AURKA, BRAF (V600E), and CHEK1 as key genes overlapping between curcumin-associated targets and TNBC-related targets. According to molecular docking, Curcumin displayed favorable binding affinities toward these targets, comparable to reference inhibitors. Stable protein-curcumin complexes with improved conformational stability were shown by molecular dynamics simulations. Strong binding free energies have been identified by MM/PBSA calculations for curcumin-CHEK1 (-209.37 kJ/mol) and curcumin-BRAF (V600E) (-192.87 kJ/mol), which are similar to inhibitors that have been clinically proven.

Our integrated analysis suggests that curcumin exerts multitarget inhibitory effects in TNBC by concurrently modulating mitotic regulation (via AURKA), MAPK signaling (via BRAF (V600E)), and DNA damage checkpoints (via CHEK1). Among these, CHEK1 emerged as the most thermodynamically stable and conformationally favorable binding target for curcumin, indicating its potential as a crucial mediator of curcumin's antitumor activity.