ASFV D117L hijacks KEAP1 to induce oxidative stress-dependent vascular endothelial cell death
4 affiliations
- 1College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province China
- 2State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Lanzhou University, Chinese Academy of Agricultural Sciences, Lanzhou, 730046 China
- 3Department of Pharmaceutical Sciences, Division of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, Vienna, 1090 Austria
- 4Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046 China
Abstract
African swine fever (ASF), caused by the ASF virus (ASFV), is a fatal hemorrhagic disease of domestic pigs that causes significant economic losses in the global pig industry. Systemic hemorrhages and abnormal coagulation of multiple tissues and organs are the typical lesions of ASFV infection, but the mechanism is still unknown. The exaggerated inflammation caused by ASFV infection is believed to contribute to endothelial injury and coagulopathy. Here, we demonstrate that circulating endothelial cells are significantly elevated in ASFV-infected pigs. In vitro infection assay shows that both primary and immortalized endothelial cells are permissive for ASFV replication, and ASFV infection triggers apoptosis of infected cells. ASFV disrupts redox homeostasis by negatively regulating the NRF2 pathway, which in turn leads to oxidative stress and ROS-mediated endothelial cell apoptosis. Mechanistically, ASFV D117L suppresses NRF2 signaling by interacting with KEAP1 and promoting the ubiquitination of NRF2. Functional analyses reveal that KEAP1 acts as a proviral factor for ASFV infection in endothelial cells, whereas its substrate, NRF2, suppresses viral replication. Further, pharmacological inhibition of KEAP1 by 4-Octyl itaconate (4-OI) and Sulforaphane (SFN) inhibits ASFV replication and ROS-dependent cell death. Our findings uncover a potential mechanism for endothelial dysfunction during ASFV infection and suggest that targeting KEAP1 to maintain endothelial redox homeostasis could be a promising approach for ASF treatment.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00018-026-06380-1.
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BibTeX
@article{han2026asfv,
title = {{ASFV D117L hijacks KEAP1 to induce oxidative stress-dependent vascular endothelial cell death}},
author = {Yumei Han and Fayu Yang and Wenchao Xue and Tianxing Cao and Xiaoyun Li and Kunpeng Zhang and Yuxuan Li and Zhonghui Zhang and Zhengshan Feng and Huanan Liu and Zhengwang Shi and Weijun Cao and Jun Zhao and Elke H Heiss and Haixue Zheng and Zixiang Zhu and Shilei Zhang},
journal = {Cellular and Molecular Life Sciences: CMLS},
year = {2026},
month = aug,
doi = {10.1007/s00018-026-06380-1},
url = {https://doi.org/10.1007/s00018-026-06380-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - ASFV D117L hijacks KEAP1 to induce oxidative stress-dependent vascular endothelial cell death
AU - Yumei Han
AU - Fayu Yang
AU - Wenchao Xue
AU - Tianxing Cao
AU - Xiaoyun Li
AU - Kunpeng Zhang
AU - Yuxuan Li
AU - Zhonghui Zhang
AU - Zhengshan Feng
AU - Huanan Liu
AU - Zhengwang Shi
AU - Weijun Cao
AU - Jun Zhao
AU - Elke H Heiss
AU - Haixue Zheng
AU - Zixiang Zhu
AU - Shilei Zhang
PY - 2026
DA - 2026/08/08
JO - Cellular and Molecular Life Sciences: CMLS
DO - 10.1007/s00018-026-06380-1
UR - https://doi.org/10.1007/s00018-026-06380-1
AB - African swine fever (ASF), caused by the ASF virus (ASFV), is a fatal hemorrhagic disease of domestic pigs that causes significant economic losses in the global pig industry. Systemic hemorrhages and abnormal coagulation of multiple tissues and organs are the typical lesions of ASFV infection, but the mechanism is still unknown. The exaggerated inflammation caused by ASFV infection is believed to contribute to endothelial injury and coagulopathy. Here, we demonstrate that circulating endothelial cells are significantly elevated in ASFV-infected pigs. In vitro infection assay shows that both primary and immortalized endothelial cells are permissive for ASFV replication, and ASFV infection triggers apoptosis of infected cells. ASFV disrupts redox homeostasis by negatively regulating the NRF2 pathway, which in turn leads to oxidative stress and ROS-mediated endothelial cell apoptosis. Mechanistically, ASFV D117L suppresses NRF2 signaling by interacting with KEAP1 and promoting the ubiquitination of NRF2. Functional analyses reveal that KEAP1 acts as a proviral factor for ASFV infection in endothelial cells, whereas its substrate, NRF2, suppresses viral replication. Further, pharmacological inhibition of KEAP1 by 4-Octyl itaconate (4-OI) and Sulforaphane (SFN) inhibits ASFV replication and ROS-dependent cell death. Our findings uncover a potential mechanism for endothelial dysfunction during ASFV infection and suggest that targeting KEAP1 to maintain endothelial redox homeostasis could be a promising approach for ASF treatment. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00018-026-06380-1.
SN - 1420-682X
SN - 1420-9071
ER -