2. Academic Validation
  3. Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication

Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication

  • Virulence. 2025 Dec;16(1):2585639. doi: 10.1080/21505594.2025.2585639.
Ying-Xian Ma 1 2 3,  Jia-Ming Yang 4,  Hang-Tian Mei 1 2 3,  Lei Zeng 1 2 3,  Guo-Yu Yang 2 3,  Jiang Wang 1 2 3 5,  Sheng-Li Ming 1 2 3,  Bei-Bei Chu 1 2 3 5 6 7
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China.
  • 2 Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan, China.
  • 3 Key Laboratory of Veterinary Biotechnology of Henan Province, Henan Agricultural University, Zhengzhou, Henan, China.
  • 4 State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 5 Key Laboratory for Animal Pathogens and Biosafety, Ministry of Education, Zhengzhou, Henan, China.
  • 6 Longhu Advanced Immunization Laboratory, Henan agricultural University, Zhengzhou, Henan, China.
  • 7 International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, Henan, China.
PMID: 41204699 DOI: 10.1080/21505594.2025.2585639
Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV), a highly contagious pathogen in swine, poses significant economic challenges to global pork production. This study elucidated the regulatory interplay between PRRSV Infection and the pentose phosphate pathway (PPP), a critical metabolic axis for anabolism. Comparative metabolomic profiling of porcine alveolar macrophages (PAMs) pre- and post-PRRSV Infection demonstrated marked upregulation of PPP activity, concomitant with elevated levels of nucleotide biosynthesis. This metabolic shift was driven by PRRSV-induced upregulation of glucose-6-phosphate dehydrogenase (G6PD), the PPP's rate-limiting enzyme. Mechanistic investigations revealed that PRRSV Infection stimulated hypoxia-inducible factor 1α (HIF-1α) expression, which transcriptionally activates G6PD. Genetic silencing of HIF-1α abolished PRRSV-mediated G6PD induction. Furthermore, Reactive Oxygen Species (ROS) accumulation was identified as the upstream regulator of HIF-1α activation during PRRSV Infection. Pharmacological ROS scavenging disrupted the ROS/HIF-1α/G6PD signaling cascade, diminished NADPH and reduced glutathione production, and consequently attenuated viral proliferation. These results established that PRRSV exploited the ROS/HIF-1α axis to reprogram host glucose metabolism through PPP potentiation, creating a biosynthetic environment conducive to viral propagation.

Keywords

G6PD; HIF-1α; PPP; PRRSV; ROS.

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