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  3. Poly-L-arginine induces asthma pyroptosis in lung epithelial cells by promoting nuclear translocation of the PKM2 dimer

Poly-L-arginine induces asthma pyroptosis in lung epithelial cells by promoting nuclear translocation of the PKM2 dimer

  • Cell Signal. 2025 Aug 21:112066. doi: 10.1016/j.cellsig.2025.112066.
Shuang Chang 1,  Xiaoxia Feng 2,  Xu Chen 3,  Min Pan 1,  Xueqin Jiang 4,  Zhangyan Ke 4,  Xingyu Yang 3,  Minglong Guan 5,  Xiaojun Zha 6,  Lingling Zhang 7,  Xiaoyun Fan 8
Affiliations

Affiliations

  • 1 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China; Anhui Geriatric Institute, Hefei 230031, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230031, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation, Hefei 230031, China.
  • 2 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China; Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230031, China; Anhui Geriatric Institute, Hefei 230031, China.
  • 3 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China; Anhui Geriatric Institute, Hefei 230031, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230031, China.
  • 4 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China; Anhui Geriatric Institute, Hefei 230031, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation, Hefei 230031, China.
  • 5 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China.
  • 6 Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230031, China.
  • 7 Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230031, China. Electronic address: ll-zhang@hotmail.com.
  • 8 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China; Anhui Geriatric Institute, Hefei 230031, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation, Hefei 230031, China. Electronic address: 13956988552@126.com.
PMID: 40848938 DOI: 10.1016/j.cellsig.2025.112066
Abstract

Inflammation is a principal mechanism in asthma pathogenesis. Activated eosinophils (EOSs) play an important role in the chronic inflammatory environment of asthma by releasing major basic protein (MBP) and Other cationic granule proteins. Pyroptosis has been demonstrated to participate in asthma-related inflammation. Recent studies have reported the involvement of Pyruvate Kinase M2 (PKM2) in inflammation development, but its precise mechanism remains elusive. In this study, the levels of PKM2 and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) messenger ribonucleic acids (mRNAs) in peripheral blood were observed to have a positive correlation with the eosinophil count in clinical samples from asthma patients. In addition, Pyroptosis was detected in not only a chronic asthma mouse model induced by Ovalbumin (OVA) but also lung epithelial cell lines treated with Poly-L-arginine (PLA), which is a mimic of MBP. Subsequent TEPP-46 (a PKM2 activator) treatment contributed to the alleviation of Pyroptosis. PLA up-regulated the expression of PKM2 and promoted the translocation of PKM2 dimers to the nucleus of lung epithelial cells. Therefore, it was hypothesized that targeting the regulation of PKM2 dimer nuclear translocation to reduce Pyroptosis may provide innovative therapeutic principles for asthma. After treatment of cells with rapamycin, an inhibitor of mTORC1, inhibition of mTORC1 resulted in a decrease in PLA-induced PKM2 expression. Therefore, we hypothesize that reducing pyrodeath by regulating PKM2 dimer nuclear translocation may provide an innovative therapeutic principle for the treatment of asthma.

Keywords

Asthma; Lung epithelial cells; PKM2; PLA; Pyroptosis.

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