Apatinib induced ferroptosis by lipid peroxidation in gastric cancer



Apatinib, a competitive inhibitor of VEGFR2, has anti-angiogenesis and anticancer activities through different mechanisms, but it still cannot fully explain the drug efficacy of apatinib. Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in cancer biology, however, the exact role of ferroptosis in apatinib-mediating anticancer treatment are still not clear.


The effects of (1S, 3R)-RSL3 and apatinib were evaluated in different GC cell lines and in normal human gastric epithelial cells. Further, the effects of apatinib and inhibition of antioxidant defense enzyme glutathione peroxidase (GPX4) on cell viability, cell death, glutathione (GSH) levels, lipid ROS production, cellular malondialdehyde (MDA) levels and protein expression were evaluated in vitro as well as in a mouse tumor xenograft model. The expression level of GPX4 in GC tissues and paracancerous tissues was measured by immunohistochemistry.


(1S, 3R)-RSL3 selectively killed GC cells, but not normal cells. Apatinib induced ferroptosis in GC cells by decreasing cellular GSH levels and increasing lipid peroxidation levels. This effect was blocked by co-incubation with ferrostatin-1, liproxstatin-1, GSH, or vitamin E. Further investigation revealed that apatinib down-regulated GPX4 expression via inhibition of the transcription factors Sterol regulatory element-binding protein-1a (SREBP-1a). Besides, we found that multi-drug resistant GC cells were vulnerable to apatinib-induced GPX4 inhibition.


In summary, we show that apatinib could induce the lipid peroxidation through GPX4 mediated by SREBP-1a, then negatively regulate the GC cell, even the multi-drug-resistant GC cell, ferroptosis.

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Gastric cancer


Glutathione peroxidase 4




Glutathione disulfide


Reactive oxygen species


RAS-selective lethal3










Short interfering RNA


Phosphate-buffered saline


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This work was supported by the National Natural Science Foundation of China (81772133 to QM and 81902444 to LYZ); the Guangdong Natural Science Fund (2020A1515010269 to LYZ and 2020A1515011367 to QM); the Guangzhou Citizen Health Science and Technology Research Project (201803010034 to QM and 201903010072 to LYZ).

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QM, GXL, and LYZ conceived of and designed the experiments. LYZ, YMP, SXH, RL, ZQW, JHH, and XTL performed the experiments. LYZ, YMP and SXH analyzed the data. QM contributed reagents/materials/analysis tools. LYZ and YMP wrote the draft, and made all revisions. All authors read and approved the final manuscript.

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Correspondence to Guoxin Li.

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Zhao, L., Peng, Y., He, S. et al. Apatinib induced ferroptosis by lipid peroxidation in gastric cancer. Gastric Cancer (2021). https://doi.org/10.1007/s10120-021-01159-8

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  • Gastric cancer
  • Apatinib
  • Ferroptosis
  • GPX4
  • Lipid peroxidation