Curcumin (Cur),an active ingredient from the rhizome of the plant,Curcuma longa,has wide anticancer activities.However,due to its poor solubility and hence poor absorption,Cur has limited clinical applications.It is therefore important to develop an effective method to improve its absorption.Natural borneol(NB),a terpene and bicyclic organic compound,has been extensively used as a food additive and our previous studies show that it can improve the uptake of Cur in cancer cells.However,the anticancer mechanism of NB/Cur remains unclear.In this study,the effects of NB/Cur on HepG2 cells were investigated by proteomic analysis.The results showed that 32 differentially expressed proteins identified by MALDI-TOF-MS were significantly changed after NB/Cur treated HepG2 cells for 24 h.Moreover,17 proteins increased and 12 proteins decreased significantly.Biological progress categorization demonstrated that the identified proteins were mainly associated with cell cycle and apoptosis (28.1%).Subcellular location categorization exhibited that the identified proteins were mainly located in nucleus (28.1%) and mitochondrion (21.9%).Among of all proteins,we selected three differentially proteins (hnRNPC1/C2,NPM and PSMA5),which were associated with the p53 pathway.Down-regulation of hnRNPC1/C2 and NPM contributed to the enhancement of phosphorylated p53.Activated p53 and down-regulation of PSMA5 resulted in an increase in p21 protein.Further studies showed that NB/Cur induced reactive oxygen species (ROS) generation,indicating that ROS might be upstream of the G2/M arrest signaling pathway.In summary,the results exhibited that the whole proteomic response of HepG2 cells to NB/Cur,which might lead to a better understanding of its underlying anticancer mechanisms.