2. Academic Validation
  3. Klebsiella pneumoniae Induces Ferroptosis and Lactation Dysfunction in Bovine Mastitis via NCOA4-Mediated Ferritinophagy

Klebsiella pneumoniae Induces Ferroptosis and Lactation Dysfunction in Bovine Mastitis via NCOA4-Mediated Ferritinophagy

  • J Agric Food Chem. 2025 Sep 24;73(38):24326-24342. doi: 10.1021/acs.jafc.5c07326.
Peng Mao 1 2 3,  Zhihao Wang 1 2 3 4,  Jiangyao Duan 1 2 3,  Pengfei Dong 1 2 3,  Changning Yuan 1 2 3,  Kangjun Liu 1 2 3,  Long Guo 1 2 3,  Luying Cui 1 2 3,  Junsheng Dong 1 2 3,  Xia Meng 1 2 3,  Guoqiang Zhu 1 2 3,  Jianji Li 1 2 3,  Heng Wang 1 2 3
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 225009, China.
  • 2 International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou 225009, China.
  • 3 Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou 225009, China.
  • 4 Affiliated Hospital of Yangzhou University, Yangzhou 225009, China.
PMID: 40937759 DOI: 10.1021/acs.jafc.5c07326
Abstract

Klebsiella pneumoniae, a major bovine mastitis pathogen, disrupts mammary gland function through poorly understood mechanisms. This study demonstrates that K. pneumoniae Infection triggers Ferroptosis in bovine mammary epithelial cells (BMECs) via nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, leading to lactation impairment. RNA Sequencing revealed enrichment in Ferroptosis, Autophagy, and iron metabolism pathways. Infection time-dependently suppressed Glutathione Peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression, causing mitochondrial membrane potential collapse and lipid peroxidation. Crucially, K. pneumoniae activated NCOA4-dependent ferritin degradation, elevating intracellular Fe2+. NCOA4 knockdown alleviated Ferroptosis, restored GPX4/SLC7A11 expression, reduced the Bacterial load, and partially rescued lactation markers (fatty acid synthase, Acetyl-CoA Carboxylase 1, and β-casein). In vivo, infected mammary glands showed iron overload, 4-hydroxynonenal accumulation, lactation protein suppression, and pathological damage, correlating with NCOA4/ferritin heavy chain 1 upregulation. These findings establish NCOA4-mediated ferritinophagy as a key driver of K. pneumoniae-induced Ferroptosis and lactation dysfunction, suggesting novel therapeutic targets for mastitis.

Keywords

Klebsiella pneumoniae; NCOA4; bovine mastitis; ferritinophagy; ferroptosis; lactation dysfunction.

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