Nrf2 Promotes BHBA-Induced Pyroptosis in Bovine Endometrial Epithelial Cells by Modulating Autophagy Mediated through Oxidative Stress

  • J Agric Food Chem. 2025 Nov 5;73(44):28126-28142. doi: 10.1021/acs.jafc.5c09896.
Jiajia Mu  1  2  3 ,  Qiannan Sun  4  5 ,  Nanyan Lin  1  2  3 ,  Khan Ishrat  6 ,  Tian Tian  1  2  3 ,  Chenguang Yue  1  2  3 ,  Xishuai Tong  1  2  3 ,  Jiaqiao Zhu  1  2  3 ,  Hui Zou  1  2  3 ,  Hongyan Zhao  1  2  3 ,  Ruilong Song  1  2  3 ,  Jianhong Gu  1  2  3 ,  Yan Yuan  1  2  3 ,  Jianchun Bian  1  2  3 ,  Zongping Liu  1  2  3 ,  Yonggang Ma  1  2  3
Affiliations
  • 1. College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P. R. China.
  • 2. Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, P. R China.
  • 3. Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, P. R China.
  • 4. Medical Research Center, Northern Jiangsu People's Hospital, Yangzhou 225001, China.
  • 5. Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China.
  • 6. Sindh Agriculture University, Tando Jam 70060, Pakistan.
PMID: 41134715 DOI: 10.1021/acs.jafc.5c09896
Abstract

Ketotic cows exhibit a heightened secondary endometritis risk through an unknown mechanism. We investigated the role of Nrf2 in ketosis-induced endometritis. Uterine tissues from ketotic cows showed higher levels of Caspase-1 and GSDMD but lower levels of Nrf2 and LC3. β-Hydroxybutyrate (BHBA) treatment induced Pyroptosis in bovine endometrial epithelial cells (BEECs), upregulated pyroptosis-related proteins, and increased the rate of Pyroptosis. Nrf2 and its downstream oxidative stress proteins were decreased, and autophagic flux was blocked. NAC, Rapa, and Nrf2 activators alleviated BHBA-induced Pyroptosis by promoting autophagic flux. In a mouse ketosis model, intervention with NAC significantly reduced blood levels of BHBA and pro-inflammatory cytokines, and the expression of pyroptosis-related proteins in uterine tissues was decreased compared with ketotic model mice. Overall, Nrf2 promoted BHBA-induced Pyroptosis in BEECs by modulating Autophagy mediated by oxidative stress, suggesting that it may serve as a potential therapeutic target.

Keywords
BHBA; Nrf2; autophagy; endometritis; ketosis; oxidative stress; pyroptosis.
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