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

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.