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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

PDHA1 Hyperactivation-Mediated Glucose Metabolism Reprogramming Fuels Neutrophil NETosis and Promotes Acute Lung Injury.

  • Yu-Biao Liu1,2
  • Wen-Jing Zhong3
  • Chen-Yu Zhang4,5,6
  • Meng-Rui Chen4,5,6
  • Nan-Shi-Yu Yang4,5,6
  • Han-Xi Sha4
  • Yan-Ling Qiu4,5,6
  • Hui Chen4,5,6
  • Jin-Tong Yang6
  • Li-Ying Liang4,5,6
  • Jian-Bing Xiong7
  • Shao-Kun Liu8
3 more authors
  • Cha-Xiang Guan1,9
  • Jia-Xi Duan1,10
  • Yong Zhou4,5,6
10 affiliations
  1. 1Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  2. 2School of Nursing, Shandong Xiehe University, Jinan, Shandong, China.
  3. 3Xiangya Nursing School, Central South University, Changsha, Hunan, China.
  4. 4Department of Physiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
  5. 5Basic and Clinical Research in Major Respiratory Disease, Key Laboratory of General University of Hunan Province, Changsha, Hunan, China.
  6. 6National Experimental Teaching Demonstration Center For Medical Function, Changsha, Hunan, China.
  7. 7Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  8. 8Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  9. 9School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia, China.
  10. 10National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Abstract

Neutrophil extracellular trap (NET) formation, termed NETosis, is a key driver of lung tissue injury in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the precise mechanisms that trigger neutrophil NETosis remain incompletely understood. Here, we observed that neutrophils from both ALI mice and ARDS patients exhibited NETosis alongside a pronounced selective metabolic shift, characterized by enhanced oxidative phosphorylation (OXPHOS) and attenuated glycolytic activity. Phosphoproteomic profiling revealed that this shift was driven by aberrant activation of pyruvate dehydrogenase E1 subunit alpha (PDHA1), resulting from its dephosphorylation at Ser293. Inhibiting PDHA1 activity, using either the inhibitor 3-fluoropyruvate (3-FP) or genetic knockdown, effectively reversed this selective metabolic reprogramming and suppressed NETosis. We further constructed neutrophil-targeted 3-FP-loaded albumin nanoparticles (3-FP-BSA NPs). These nanoparticles were specifically taken up by activated neutrophils, markedly inhibited NETosis, and alleviated lipopolysaccharide-induced ALI in mice. Mechanistically, RNA-seq revealed the enrichment of the AMPK in neutrophils during NETosis. AMPK phosphorylated PDHA1 at Ser314, which disrupted the PDHA1-pyruvate dehydrogenase kinase 1 (PDK1) interaction and inhibited PDHA1 phosphorylation at Ser293. Ultimately, PDHA1 hyperactivation-driven selective metabolic reprogramming precipitated mitochondrial stress and mtROS accumulation, thereby initiating NETosis. This study defines a targetable metabolic pathway in neutrophils and advances a specific PDHA1-nanotherapeutic strategy against ALI/ARDS.

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Cite

BibTeXRIS
BibTeX
@article{liu2026pdha1,
  title = {{PDHA1 Hyperactivation-Mediated Glucose Metabolism Reprogramming Fuels Neutrophil NETosis and Promotes Acute Lung Injury.}},
  author = {Yu-Biao Liu and Wen-Jing Zhong and Chen-Yu Zhang and Meng-Rui Chen and Nan-Shi-Yu Yang and Han-Xi Sha and Yan-Ling Qiu and Hui Chen and Jin-Tong Yang and Li-Ying Liang and Jian-Bing Xiong and Shao-Kun Liu and Cha-Xiang Guan and Jia-Xi Duan and Yong Zhou},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78307},
  url = {https://europepmc.org/article/MED/42875839},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - PDHA1 Hyperactivation-Mediated Glucose Metabolism Reprogramming Fuels Neutrophil NETosis and Promotes Acute Lung Injury.
AU  - Yu-Biao Liu
AU  - Wen-Jing Zhong
AU  - Chen-Yu Zhang
AU  - Meng-Rui Chen
AU  - Nan-Shi-Yu Yang
AU  - Han-Xi Sha
AU  - Yan-Ling Qiu
AU  - Hui Chen
AU  - Jin-Tong Yang
AU  - Li-Ying Liang
AU  - Jian-Bing Xiong
AU  - Shao-Kun Liu
AU  - Cha-Xiang Guan
AU  - Jia-Xi Duan
AU  - Yong Zhou
PY  - 2026
DA  - 2026/10/14
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78307
UR  - https://europepmc.org/article/MED/42875839
AB  - Neutrophil extracellular trap (NET) formation, termed NETosis, is a key driver of lung tissue injury in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the precise mechanisms that trigger neutrophil NETosis remain incompletely understood. Here, we observed that neutrophils from both ALI mice and ARDS patients exhibited NETosis alongside a pronounced selective metabolic shift, characterized by enhanced oxidative phosphorylation (OXPHOS) and attenuated glycolytic activity. Phosphoproteomic profiling revealed that this shift was driven by aberrant activation of pyruvate dehydrogenase E1 subunit alpha (PDHA1), resulting from its dephosphorylation at Ser293. Inhibiting PDHA1 activity, using either the inhibitor 3-fluoropyruvate (3-FP) or genetic knockdown, effectively reversed this selective metabolic reprogramming and suppressed NETosis. We further constructed neutrophil-targeted 3-FP-loaded albumin nanoparticles (3-FP-BSA NPs). These nanoparticles were specifically taken up by activated neutrophils, markedly inhibited NETosis, and alleviated lipopolysaccharide-induced ALI in mice. Mechanistically, RNA-seq revealed the enrichment of the AMPK in neutrophils during NETosis. AMPK phosphorylated PDHA1 at Ser314, which disrupted the PDHA1-pyruvate dehydrogenase kinase 1 (PDK1) interaction and inhibited PDHA1 phosphorylation at Ser293. Ultimately, PDHA1 hyperactivation-driven selective metabolic reprogramming precipitated mitochondrial stress and mtROS accumulation, thereby initiating NETosis. This study defines a targetable metabolic pathway in neutrophils and advances a specific PDHA1-nanotherapeutic strategy against ALI/ARDS.
SN  - 2198-3844
ER  -