Targeting the STAT3/ACLY axis attenuates pulmonary inflammation but delays Mycoplasma pneumoniae clearance via citrate metabolism

Authors:
Publisher website
Google Scholar
Abstract
Airway epithelial cells play a pivotal role in the early host response to Mycoplasma pneumoniae colonization. Our previous study has revealed that M. pneumoniae infection induces metabolic reprogramming in bronchial epithelial cells. However, the mechanisms underlying these metabolic shifts and their contribution to the pathogenesis of pneumonia remain unclear. Herein, we demonstrate that M. pneumoniae infection activates signal transducer and activator of transcription 3 (STAT3), which drives citrate accumulation in airway epithelial cells. Citrate is metabolized by adenosine triphosphate-citrate lyase (ACLY) into acetyl coenzyme A, which is further converted to malonyl coenzyme A, promoting post-translational modifications such as histone acetylation and glyceraldehyde-3-phosphate dehydrogenase malonylation (GAPDH). In vivo, pharmacological inhibition of STAT3 or ACLY attenuated pulmonary inflammation and pro-inflammatory cytokine expression yet paradoxically delayed pathogen clearance, as evidenced by increased colonyforming units in bronchoalveolar lavage fluid and lung tissue. These findings demonstrate that targeting the STAT3/ACLY axis exerts antiinflammatory potential without direct antibacterial activity. Our work highlights the dual regulatory roles of citrate metabolism in inflammation and pathogen control and suggests that combined use of STAT3/ACLY inhibitors with conventional antibiotics may be necessary to achieve both immunomodulation and effective bacterial eradication.
Funding Information
  • Technology Innovation Project Plan of Health System of Shanghai Putuo District (ptkwws202314)
  • Research Project Plan of the Shanghai Putuo People’s Hospital (2022rmky02)
  • Graduate student scientific research innovation projects in Hunan province (CX20240844)
  • Clinical medical technology innovation guidance project of Hunan Province (2021SK51906)
  • Natural Science Foundation of Hunan Province (2023JJ60046)
  • Natural Science Foundation of Hunan Province (2024JJ9389)
  • Scientific Research Project of Hunan Provincial Health Committee (20230954)
  • Scientific Research Fund of Education Department of Hunan Province (22A0288)
  • Science and Technology Innovation Project of Hengyang (202330046180)

This publication has 35 references indexed in Scilit: