Hypoxia inducible factor-1α drives cancer resistance to cuproptosis

Zhou Yang; Wei Su; Xiyi Wei; Yitong Pan; Mengying Xing; Lili Niu; Baijie Feng; Weiyu Kong; Xiaohan Ren; Feng Huang; Jingwan Zhou; Wei Zhao; Yingyi Qiu; Tian Liao; Qi Chen; Shuang Qu; Yunjun Wang; Qing Guan; Duanshu Li; Ke Zen; Yun Chen; Chao Qin; Yu Wang; Xiang Zhou; Jun Xiang; Bing Yao

doi:10.1016/j.ccell.2025.02.015

Hypoxia inducible factor-1α drives cancer resistance to cuproptosis

Cancer Cell. 2025 Mar 4:S1535-6108(25)00067-4. doi: 10.1016/j.ccell.2025.02.015. Online ahead of print.

Authors

Zhou Yang¹, Wei Su², Xiyi Wei³, Yitong Pan⁴, Mengying Xing⁵, Lili Niu⁶, Baijie Feng⁷, Weiyu Kong³, Xiaohan Ren³, Feng Huang⁸, Jingwan Zhou⁸, Wei Zhao⁹, Yingyi Qiu⁸, Tian Liao¹, Qi Chen¹, Shuang Qu¹⁰, Yunjun Wang¹, Qing Guan¹, Duanshu Li¹, Ke Zen⁵, Yun Chen¹¹, Chao Qin¹², Yu Wang¹³, Xiang Zhou¹⁴, Jun Xiang¹⁵, Bing Yao¹⁶

Affiliations

¹ Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
³ Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁴ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
⁵ The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
⁶ Department of Integrative Medicine, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University, Shanghai, China.
⁷ Department of Medical Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
⁸ National Experimental Teaching Center of Basic Medical Science, Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
⁹ Department of Clinical Laboratory, School of Clinical Medicine and the First Affiliated Hospital of Chengdu Medical College, Department of Clinical Biochemistry, School of Laboratory Medicine, Chengdu Medical College, Chengdu, China.
¹⁰ Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
¹¹ Research Center of Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China; Department of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: chenyun@njmu.edu.cn.
¹² Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: qinchao@njmu.edu.cn.
¹³ Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: neck130@hotmail.com.
¹⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: xiangzhou@fudan.edu.cn.
¹⁵ Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: xiangjun@shca.org.cn.
¹⁶ National Experimental Teaching Center of Basic Medical Science, Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Department of General Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, NHC Key Laboratory of Antibody Technique, Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China. Electronic address: byao@njmu.edu.cn.

PMID: 40054467
DOI: 10.1016/j.ccell.2025.02.015

Abstract

Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis in vivo. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.

Keywords: cuproptosis; hypoxia; hypoxia inducible factor-1α; lipoylation; solid tumors.