Medicinal plants have long been an excellent source of pharmaceutical agents.Autophagy, a catabolic degradation process through lysosomes, plays an important role in tumorigenesis and cancer therapy.Through a screen designed to identify autophagic regulators from a library of natural compounds, we found that Guttiferone K (GUTK) can activate autophagy in several cancer cell lines.Exposure to GUTK was observed to markedly induce GFP-LC3 puncta formation and activate the accumulation of LC3-Ⅱ and the degradation of p62 in HeLa cells,which was also detected in Capan-2 and CNE cells after GUTK treatment, suggesting that GUTK is an autophagy inducer.Cancer cells show an inherent ability to tolerate extreme conditions, such as low nutrient and oxygen supplies, by modulating their energy metabolism.Thus, targeting nutrient-deprived cancer cells may be a novel strategy in anticancer drug development because interfering with autophagy may sensitize cancer cells to nutrient starvation-induced cell death.We then investigated whether GUTK plays a role in Earles Balanced Salt Solution (EBSS)-induced cell death in HeLa cells.Interestingly, we found that GUTK can rapidly induce cell death in nutrient-deprived conditions.Importantly,hydroxychloroquine, an autophagy inhibitor, was found to significantly prevent GUTK-induced cell death in nutrient starvation conditions.In contrast, the pan-caspase inhibitor z-VAD-fmk only partially prevented the cell death caused by GUTK in EBSS.suggesting that the cell death observed is largely dependent on autophagy.The Akt-mTOR signalling pathway is an important negative regulator of autophagy.We found that GUTK significantly decreased the phosphorylation of Akt, thereby inhibiting the mTOR pathway in cancer cells during nutrient starvation.In addition, GUTK causes the accumulation of reactive oxygen species (ROS) and the phosphorylation of JNK in EBSS, which may contribute to the mechanism through which GUTK affects autophagy.Collectively, these data propose that cells under nutrient stress are more sensitive to GUTK, which may indicate its potential for anticancer drug development.