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Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription

Acta Pharmacologica Sinica volume 44, pages 1712–1724 (2023)Cite this article

Abstract

A number of studies have shown that aspirin, as commonly prescribed drug, prevents the development of hepatocellular carcinoma (HCC). Ferroptosis as a dynamic tumor suppressor plays a vital role in hepatocarcinogenesis. In this study we investigated whether aspirin affected ferroptosis in liver cancer cells. RNA-seq analysis revealed that aspirin up-regulated 4 ferroptosis-related drivers and down-regulated 5 ferroptosis-related suppressors in aspirin-treated HepG2 cells. Treatment with aspirin (4 mM) induced remarkable ferroptosis in HepG2 and Huh7 cells, which was enhanced by the ferroptosis inducer erastin (10 μM). We demonstrated that NF-κB p65 restricted ferroptosis in HepG2 and Huh7 cells through directly binding to the core region of SLC7A11 promoter and activating the transcription of ferroptosis inhibitor SLC7A11, whereas aspirin induced ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription. Overexpression of p65 rescued HepG2 and Huh7 cells from aspirin-induced ferroptosis. HCC patients with high expression levels of SLC7A11 and p65 presented lower survival rate. Functionally, NF-κB p65 blocked the aspirin-induced ferroptosis in vitro and in vivo, which was attenuated by erastin. We conclude that aspirin triggers ferroptosis by restricting NF-κB-activated SLC7A11 transcription to suppress the growth of HCC. These results provide a new insight into the mechanism by which aspirin regulates ferroptosis in hepatocarcinogenesis. A combination of aspirin and ferroptosis inducer may provide a potential strategy for the treatment of HCC in clinic.

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Fig. 1: Aspirin is involved in ferroptosis in HCC cells.
Fig. 2: Aspirin triggers ferroptosis in HCC cells.
Fig. 3: The NF-κB p65 restricts ferroptosis in liver cancer cells.
Fig. 4: Aspirin induces ferroptosis through NF-κB p65 in HCC cells.
Fig. 5: Aspirin induces ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription in cancer cells.
Fig. 6: Aspirin confers p65-mediated ferroptosis to inhibit the growth of cancers in vitro and in vivo.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (No. 82103066, No. 81872184), China Postdoctoral Science Foundation (No. 2022M712389) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A).

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  1. These authors contributed equally: Yu-fei Wang, Jin-yan Feng, Li-na Zhao, Man Zhao

Authors and Affiliations

  1. Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China

    Yu-fei Wang, Li-na Zhao, Hong-feng Yuan, Chun-yu Hou, Hui-hui Zhang, Guang Yang & Xiao-dong Zhang

  2. Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, China

    Yu-fei Wang, Jin-yan Feng, Li-na Zhao, Xian-fu Wei, Hong-feng Yuan, Chun-yu Hou, Hui-hui Zhang, Guo-wen Wang, Guang Yang & Xiao-dong Zhang

  3. Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China

    Jin-yan Feng, Xian-fu Wei & Guo-wen Wang

  4. Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China

    Man Zhao & Yu Geng

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Contributions

YFW, JYF, and LNZ performed most of the experiments. MZ, XFW, YG, HFY, CYH, and HHZ performed some experiments. XDZ, GY, GWW and YFW designed the experiments. XDZ and YFW interpreted the results. XDZ and YFW wrote the paper with help from all authors.

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Correspondence to Guo-wen Wang, Guang Yang or Xiao-dong Zhang.

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Wang, Yf., Feng, Jy., Zhao, Ln. et al. Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription. Acta Pharmacol Sin 44, 1712–1724 (2023). https://doi.org/10.1038/s41401-023-01062-1

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