These observations suggest that the cytoxicity in liver NK cells from fasted mice is linked to the specific upregulation of TRAIL by acute starvation. Our result may help understand the innate immune response in WZ4002 EGFR/HER2 inhibitor post-operative fasted and cachectic patients or patients with other conditions suffering from fasting. Besides many negative effects of starvation, such as fatigue and weight loss, fasting may still exert high level of antitumor effects via TRAIL-mediated NK cell activity. This might provide a new therapeutic approach to activate TRAIL-mediated NK cell activity in patients; further studies are needed in this regard. Many factors contribute to the regulation of TRAIL expression in NK cells. Interferon gamma is one of the most important factor, which can both induce TRAIL expression in NK cells and mediate NK cell cytotoxic activity. Other cytokines such as IL-2, IL-12, IL-15, IL-18, and IL-21 have been shown to be involved in the survival and antitumor activity of NK cells. However, neither IFN-c nor IL-12 is upregulated in 3day-fasted mice, and neither IL-12 nor IL-18 induced TRAIL expression in liver NK cells. It is well known that HSPs are strongly induced in various stressful situations to cope with stimuli. HSP60 and GRP78 were found to be induced in response to fasting. In this study, we found that HSP70 was significantly overexpressed in the liver of fasted mice. HSP70 can actively translocate into the plasma membrane following some stresses and even be released into the extracellular space to stimulate immune cells. Previous studies have shown that HSP70 is linked to NK cell cytotoxicity. Membrane-bound HSP70 on tumor cells has been identified as a recognition structure for NK cells that promotes NK cell cytotoxicity, and an in vitro study has shown that culturing NK cells with HSP70 leads to an increase in their cytotoxicity. In addition, adoptive infusion of HSP70/IL-2 pre-stimulated NK cells induced shrinking of tumor masses in tumor-bearing mice and improved survival. Despite such striking facts, it is still not fully understood which molecules are responsible for NK cell immunostimulatory response to HSP70. In the present study, we cultured recombinant HSP70 with liver lymphocytes and found that NK cell proliferation increased with HSP70 stimulation. Furthermore, both TRAIL and CD69 expression in liver NK cells from fed mice were upregulated in response to HSP70 in a dose-dependent manner. This result suggests that HSP70 may play a role in the stimulation of TRAIL expression in NK cells during fasting. Since TRAIL downregulation by HSP70 inhibition is not complete, there may be other factors that regulate TRAIL-mediated NK activity; further studies are needed in this regard. In conclusion, our mouse-model study showed that starvation has a positive effect on innate immunity by activating liver NK cells through TRAIL upregulation.