Induction of Ferroptosis by Shikonin in Gastric Cancer via the DLEU1/mTOR/GPX4 Axis

ABSTRACT Gastric cancer (GC) is the most prevalent cancer in Asia. Shikonin, one of the ingredients extracted from the roots of Lithospermum erythrorhizon , has been proven to be a necrosis inducer and has an antitumour effect on many cancers. We explored the mechanism of the antitumour effect of shikonin in GC. CCK8 and clonogenic assays were used to determine the effect of shikonin on the proliferation of GC cell lines. Shikonin could induce reactive oxygen species (ROS), lipid ROS, intracellular ferrous iron (Fe 2+ ), and malondialdehyde (MDA) in GC. We also found that shikonin decreased the expression of GPX4 by suppressing GPX4 synthesis and decreasing ferritin. Furthermore, long noncoding RNA deleted in lymphocytic leukaemia 1 (DLEU1) is an oncogene in GC, and shikonin decreased DLEU1 expression in GC cells. Overexpression of DLEU1 eliminated the anticancer effect of shikonin. Mechanistically, shikonin might decrease GPX4 levels by inhibiting the DLEU1/mTOR pathway. DLEU1 was sponged with miR‐9‐3p, which also regulated mTOR and GPX4. A xenograft tumour model of GC was established, and shikonin treatment inhibited cell proliferation and induced ferroptosis. In conclusion, shikonin exerts its antitumour effects on GC by triggering ferroptosis, and the DLEU1/mTOR/GPX4 axis may play an essential role in shikonin‐induced ferroptosis. Therefore, our findings provide a potential lead compound for treating GC.