Myricetin, a natural flavonoid, exhibits diverse biological activities, including antitumor effects. The present study aimed to investigate the effects of myricetin on hepatocellular carcinoma (HCC) cells and explore the underlying molecular mechanisms. Our results showed that myricetin significantly inhibited cell proliferation and induced apoptosis in HCC cells. The apoptosis induced by myricetin was associated with the activation of endoplasmic reticulum (ER) stress. In addition, autophagy was enhanced in response to ER stress. Inhibition of autophagy by RNA interference or chemical inhibitors resulted in increased apoptosis in myricetin-treated HCC cells. The in vivo experiment also showed that myricetin effectively reduced tumor growth in an HCC xenograft model and that combination treatment with an autophagy inhibitor significantly enhanced this effect. These results indicated that myricetin induced apoptosis in HCC cells through the activation of ER stress. Protective autophagy was also upregulated during this process. Simultaneous inhibition of autophagy enhanced the anti-HCC activity of myricetin. Myricetin might be a promising drug candidate for HCC therapy, and the combined use of myricetin with autophagy inhibitors could be an effective therapeutic strategy.
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