2. Academic Validation
  3. CISD3 inhibition drives cystine-deprivation induced ferroptosis

CISD3 inhibition drives cystine-deprivation induced ferroptosis

  • Cell Death Dis. 2021 Sep 8;12(9):839. doi: 10.1038/s41419-021-04128-2.
Yanchun Li  # 1 2,  Xin Wang  # 3,  Zhihui Huang  # 3,  Yi Zhou 4,  Jun Xia 4,  Wanye Hu 5,  Xu Wang 4,  Jing Du 6,  Xiangmin Tong 7 8 9 10,  Ying Wang 11 12 13
Affiliations

Affiliations

  • 1 Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 2 Department of Central Laboratory, Affiliated Hangzhou first people's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
  • 3 College of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
  • 4 Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 5 Bengbu Medical College, Bengbu, Anhui, 233000, China.
  • 6 Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. [email protected].
  • 7 Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. [email protected].
  • 8 Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. [email protected].
  • 9 Bengbu Medical College, Bengbu, Anhui, 233000, China. [email protected].
  • 10 Phase I Clinical Research Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. [email protected].
  • 11 Department of Central Laboratory, Affiliated Hangzhou first people's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. [email protected].
  • 12 Bengbu Medical College, Bengbu, Anhui, 233000, China. [email protected].
  • 13 Phase I Clinical Research Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. [email protected].
  • # Contributed equally.
PMID: 34497268 DOI: 10.1038/s41419-021-04128-2
Abstract

Ferroptosis, a new form of programmed cell death, not only promotes the pathological process of various human diseases, but also regulates Cancer progression. Current perspectives on the underlying mechanisms remain largely unknown. Herein, we report a member of the NEET protein family, CISD3, exerts a regulatory role in Cancer progression and Ferroptosis both in vivo and in vitro. Pan-cancer analysis from TCGA reveals that expression of CISD3 is generally elevated in various human cancers which are consequently associated with a higher hazard ratio and poorer overall survival. Moreover, knockdown of CISD3 significantly accelerates lipid peroxidation and accentuates free iron accumulation triggered by Xc- inhibition or cystine-deprivation, thus causing ferroptotic cell death. Conversely, ectopic expression of the shRNA-resistant form of CISD3 (CISD3res) efficiently ameliorates the ferroptotic cell death. Mechanistically, CISD3 depletion presents a metabolic reprogramming toward glutaminolysis, which is required for the fuel of mitochondrial oxidative phosphorylation. Both the inhibitors of glutaminolysis and the ETC process were capable of blocking the lipid peroxidation and ferroptotic cell death in the shCISD3 cells. Besides, genetic and pharmacological activation of Mitophagy can rescue the CISD3 knockdown-induced Ferroptosis by eliminating the damaged mitochondria. Noteworthily, GPX4 acts downstream of CISD3 mediated Ferroptosis, which fails to reverse the homeostasis of mitochondria. Collectively, the present work provides novel insights into the regulatory role of CISD3 in ferroptotic cell death and presents a potential target for advanced antitumor activity through Ferroptosis.

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