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Microbial pathogenesis

Microbial pathogenesis

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ACE2 mitigates Streptococcus uberis-induced ferroptosis in goat mammary epithelial cells by inhibiting ROS-chaperone-mediated autophagic degradation of GPX4

Published:30 October 2025 DOI: 10.1016/j.micpath.2025.108141 PMID: 41173434
Gang Wu, Chang Ma, Jiajing Xu, Xueqing Chen, Xiwen Chen, Gongmin Wang, Yuanshu Zhang

Abstract

Streptococcus uberis (S. uberis), is a prevalent and highly infectious environmental pathogen that exacerbates the pathological process of mastitis in lactating animals by inducing oxidative stress and cell damage. Ferroptosis, a novel form of programmed cell death, has attracted increasing attention for its potential role in the pathogenesis of mastitis caused by pathogens like S. aureus and E. coli. However, whether S. uberis infection exacerbates damage to goat mammary epithelial cells (GMECs) via ferroptosis and its underlying regulatory mechanisms remain unclear. This study found that S. uberis infection induced iron overload and lipid peroxidation, with a significant decrease in GPX4, a key regulator of ferroptosis. Further investigation revealed that S. uberis-mediated over-activation of chaperone-mediated autophagy (CMA) promoted GPX4 degradation in lysosomes, regulated by ROS levels. Additionally, S. uberis infection activated ADAM17, reducing membrane-bound ACE2 expression, and promoting the activation of the Ang II/AT1R/NOX2 pathway to induce oxidative stress. ACE2, by degrading Ang II, decreased intracellular ROS, enhanced GPX4 stability, and reduced CMA activity, alleviating ferroptosis. These findings identify ACE2 as a key regulator of the ROS-CMA-GPX4 axis during S. uberis infection, offering new insights into host defense against S. uberis-induced mastitis and highlighting ferroptosis regulation as a promising therapeutic strategy for bacterial infectious diseases.

Substances (48)

Materials
Procduct Name CAS Molecular Formula Supplier Price
N-Acetyl-L-cysteine 616-91-1 C5H9NO3S 1339 suppliers $5.00-$3143.10
N-Acetyl-L-cysteine 616-91-1 C5H9NO3S 1339 suppliers $5.00-$3143.10
N-Acetyl-L-cysteine 616-91-1 C5H9NO3S 1339 suppliers $5.00-$3143.10
N-Acetyl-L-cysteine 616-91-1 C5H9NO3S 1339 suppliers $5.00-$3143.10
Ammonium ferric citrate 1185-57-5 C6H11FeNO7 581 suppliers $5.00-$3420.00
Ammonium ferric citrate 1185-57-5 C6H11FeNO7 581 suppliers $5.00-$3420.00
Ammonium ferric citrate 1185-57-5 C6H11FeNO7 581 suppliers $5.00-$3420.00
Ammonium ferric citrate 1185-57-5 C6H11FeNO7 581 suppliers $5.00-$3420.00
Rotenone 83-79-4 C23H22O6 458 suppliers $20.00-$1460.00
Rotenone 83-79-4 C23H22O6 458 suppliers $20.00-$1460.00
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