2. Academic Validation
  3. USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway

USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway

  • Autophagy. 2024 Oct 3. doi: 10.1080/15548627.2024.2410619.
Ling Chen 1 2 3,  Jieling Ning 3 4,  Li Linghu 1 2 3,  Jun Tang 1 2 3,  Na Liu 5 6,  Yao Long 1 2 3,  Jingyue Sun 1 2 3,  Cairui Lv 1 2 3,  Ying Shi 1 2 3,  Tania Tao 1 2 3,  Desheng Xiao 2 7,  Ya Cao 3,  Xiang Wang 8,  Shuang Liu 9,  Guangjian Li 4,  Bin Zhang 10,  Yongguang Tao 1 2 3 4 7
Affiliations

Affiliations

  • 1 Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
  • 2 Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
  • 3 Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha, Hunan, China.
  • 4 Department of Thoracic Surgery I, the Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Kunming, China.
  • 5 Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 6 Postdoctoral Research Workstation, Department of Neurosurgery, Xiangya Hospital, Central South University, Hunan, China.
  • 7 Department of Pathology, School of Basic Medicine, Central South University, Changsha, China.
  • 8 Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 9 Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 10 Department of Histology and Embryology, School of Basic Medicine, Central South University, Changsha, China.
PMID: 39360581 DOI: 10.1080/15548627.2024.2410619
Abstract

Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that Autophagy is positivelyassociated with sensitivity to Ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each Other remain largely unclear. Here, we screened85 deubiquitinating Enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining Autophagy and Ferroptosis in the KRAS-mutantLUAD.

Keywords

Autophagy; LUAD; NFE2L2; SQSTM1; USP13; ferroptosis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101494
    99.94%, ERK1/ERK2抑制剂
    ERK
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z