A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Fan Yao (), Yalan Deng, Yang Zhao, Ying Mei, Yilei Zhang, Xiaoguang Liu, Consuelo Martinez, Xiaohua Su, Roberto R. Rosato, Hongqi Teng, Qinglei Hang, Shannon Yap, Dahu Chen, Yumeng Wang, Mei-Ju May Chen, Mutian Zhang, Han Liang, Dong Xie, Xin Chen, Hao Zhu, Jenny C. Chang, M. James You, Yutong Sun, Boyi Gan and Li Ma ()
Additional contact information
Fan Yao: Huazhong Agricultural University
Yalan Deng: The University of Texas MD Anderson Cancer Center
Yang Zhao: The University of Texas MD Anderson Cancer Center
Ying Mei: The University of Texas MD Anderson Cancer Center
Yilei Zhang: The University of Texas MD Anderson Cancer Center
Xiaoguang Liu: The University of Texas MD Anderson Cancer Center
Consuelo Martinez: The University of Texas MD Anderson Cancer Center
Xiaohua Su: The University of Texas MD Anderson Cancer Center
Roberto R. Rosato: Houston Methodist Hospital
Hongqi Teng: The University of Texas MD Anderson Cancer Center
Qinglei Hang: The University of Texas MD Anderson Cancer Center
Shannon Yap: The University of Texas MD Anderson Cancer Center
Dahu Chen: The University of Texas MD Anderson Cancer Center
Yumeng Wang: The University of Texas MD Anderson Cancer Center
Mei-Ju May Chen: The University of Texas MD Anderson Cancer Center
Mutian Zhang: Texas A&M University
Han Liang: The University of Texas MD Anderson Cancer Center
Dong Xie: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xin Chen: University of California San Francisco
Hao Zhu: University of Texas Southwestern Medical Center
Jenny C. Chang: Houston Methodist Hospital
M. James You: The University of Texas MD Anderson Cancer Center
Yutong Sun: The University of Texas MD Anderson Cancer Center
Boyi Gan: The University of Texas MD Anderson Cancer Center
Li Ma: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Date: 2021
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DOI: 10.1038/s41467-021-27452-9

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