2. Academic Validation
  3. ELANE enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease

ELANE enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease

  • Cell Death Dis. 2025 Apr 9;16(1):266. doi: 10.1038/s41419-025-07603-2.
Qingqing Yang # 1,  Xuan Shen # 2,  Yan Luo # 3,  Rongqing Li 4,  Xiangrui Meng 5,  Ping Xu 1,  Xuan Liu 1,  Dongxue Bian 6,  Jianhua Wang 7,  Junping Shi 8,  Jin Chen 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The First People's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China.
  • 2 College of Basic Medicine, Jiangsu Medical college, Yancheng, Jiangsu, China.
  • 3 Department of Liver Diseases, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China.
  • 4 College of Clinical Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
  • 5 Department of Nuclear Medicine, Xinxiang Central Hospital, The Fourth Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
  • 6 Department of Gastroenterology, Yancheng TCM Hospital Affiliated with Nanjing University of Chinese Medicine, Yancheng, Jiangsu, China.
  • 7 Department of Gastroenterology, The First People's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China. 290750072@qq.com.
  • 8 Department of Liver Diseases, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China. davidshi0571@126.com.
  • 9 Department of Gastroenterology, The First People's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China. chenjin0837@163.com.
  • # Contributed equally.
PMID: 40204709 DOI: 10.1038/s41419-025-07603-2
Abstract

Neutrophil Elastase (Elane) is upregulated in metabolic-associated fatty liver disease (MAFLD) and has the capacity to promote disease progression. However, the mechanism by which Elane promotes MAFLD development remains unclear. Ferroptosis, which is an iron-dependent nonapoptotic form of cell death characterized by the iron-induced accumulation of lipid Reactive Oxygen Species (ROS), has been recently considered as an important mechanism for the development of MAFLD. In this study, we used mice of Elane-knockout (Elane-KO) and wild-type (WT), and their primary mouse hepatocytes to establish MAFLD models in vivo and vitro for elucidating the role of Elane in Ferroptosis of hepatocytes and MAFLD development. Elane-KO in vivo reduced high-fat diet (HFD) induced hepatic lipid peroxidation levels and the proportion of hepatocyte death, upregulated the expression of Nrf2 and Gpx4, and downregulated Keap1 expression. Treatment with recombinant Elane increased the lipid peroxidation level of hepatocytes, increased the Ferroptosis rate of hepatocytes, upregulated the expression of Keap1, enhanced the ubiquitination of Nrf2, and downregulated the expression of Nrf2 and Gpx4 in an FFA-induced MAFLD in vitro model. However, primary hepatocytes from Elane-KO mice presented opposite changes. Furthermore, an in vitro experiment revealed that Elane enhanced the protein stability of Keap1 and thus increased Keap1 expression in hepatocytes by inhibiting the lysosomal degradation of the Keap1 protein. Finally, in vitro Co-IP experiments revealed that Elane increased the protein stability of Keap1 by weakening the binding between p62 and Keap1 and ultimately promoted hepatocyte Nrf2 ubiquitination and Ferroptosis in MAFLD. In conclusion, our results suggested that Elane promoted hepatocyte Ferroptosis in MAFLD through the P62-Keap1-Nrf2-Gpx4 axis. Elane promotes Ferroptosis in hepatocytes from fatty livers. Elane reduces the binding of p62 to Keap1, thereby increasing Keap1 protein stability and subsequently inhibiting the Nrf2/Gpx4 pathway, ultimately leading to Ferroptosis in hepatocytes.

Figures
Products
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