2. Academic Validation
  3. Klebsiella pneumoniae induced ferroptosis by inhibition of the Nrf2/xCT/GPX4 pathway in bovine mastitis: In vivo and in vitro

Klebsiella pneumoniae induced ferroptosis by inhibition of the Nrf2/xCT/GPX4 pathway in bovine mastitis: In vivo and in vitro

  • Virulence. 2025 Dec;16(1):2600142. doi: 10.1080/21505594.2025.2600142.
Peng Mao 1 2 3,  Zhihao Wang 1 2 3,  Changning Yuan 1 2 3,  Kangjun Liu 1 2 3,  Long Guo 1 2 3,  Junsheng Dong 1 2 3,  Luying Cui 1 2 3,  Jianji Li 1 2 3,  Guoqiang Zhu 1 2 3,  Xia Meng 1 2 3,  Hongyun Liu 4,  Lili Zhang 5,  Ran Wang 5,  Heng Wang 1 2
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.
  • 2 International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China.
  • 3 Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China.
  • 4 Institute of Dairy Science, Zhejiang University, Hangzhou, China.
  • 5 Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing, China.
PMID: 41343264 DOI: 10.1080/21505594.2025.2600142
Abstract

Klebsiella pneumoniae (K. pneumoniae), a prominent causative agent of mastitis in dairy cattle, remains enigmatic in its pathogenic mechanisms. This study aimed to reveal the effects of K. pneumoniae on mammary glands via the induction of Ferroptosis, as well as the protective role of Ferrostatin-1 (Fer-1) against this pathogen-mediated damage in bovine mammary epithelial cells (BMECs). Holstein cows were used to establish an intramammary Infection model of K. pneumoniae. In vitro, primary BMECs were treated with 10 μM Fer-1 and K. pneumoniae alone or in combination. The results showed that mammary glands infected with K. pneumoniae exhibited increased transcriptional levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Concurrently, significant elevations in iron, 4-hydroxynonenal, and Reactive Oxygen Species (ROS) levels were observed. Conversely, K. pneumoniae Infection downregulated nuclear factor erythroid 2-related factor 2 (Nrf2), cystine/glutamate antiporter (xCT), Glutathione Peroxidase 4 (GPX4), and glutathione levels. Following K. pneumoniae invasion, intracellular Fe2+ and lipid ROS accumulated in the BMECs, impeding activation of Nrf2/xCT/GPX4 signal transduction. Additionally, Fer-1 facilitated the nuclear translocation of Nrf2 protein, upregulating the protein levels of Nrf2/xCT/GPX4 while downregulation transcriptional levels of IL-1β, IL-6, IL-8, and TNF-α. In conclusion, Fer-1 alleviates K. pneumoniae-induced inflammatory factor activation and Ferroptosis in BMECs via upregulation of the Nrf2/xCT/GPX4 pathway, supporting Ferroptosis inhibition holds promise as a feasible therapeutic agent for the control of mastitis.

Keywords

Ferroptosis; bovine mammary epithelial cells; bovine mastitis; ferrostatin-1; klebsiella pneumoniae.

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