2. Academic Validation
  3. Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription

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

  • Acta Pharmacol Sin. 2023 Feb 24. doi: 10.1038/s41401-023-01062-1.
Yu-Fei Wang # 1 2,  Jin-Yan Feng # 2 3,  Li-Na Zhao # 1 2,  Man Zhao # 4,  Xian-Fu Wei 2 3,  Yu Geng 4,  Hong-Feng Yuan 1 2,  Chun-Yu Hou 1 2,  Hui-Hui Zhang 1 2,  Guo-Wen Wang 5 6,  Guang Yang 7 8,  Xiao-Dong Zhang 9 10
Affiliations

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.
  • 2 Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
  • 3 Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
  • 4 Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China.
  • 5 Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. wangguowen@tmu.edu.cn.
  • 6 Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China. wangguowen@tmu.edu.cn.
  • 7 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. yangguang@tjmuch.com.
  • 8 Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. yangguang@tjmuch.com.
  • 9 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. zhangxiaodong@tjmuch.com.
  • 10 Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. zhangxiaodong@tjmuch.com.
  • # Contributed equally.
PMID: 36829052 DOI: 10.1038/s41401-023-01062-1
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.

Keywords

NF-κB; PDTC; SLC7A11; aspirin; erastin; ferroptosis; ferrostatin-1; hepatocellular carcinoma.

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