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

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.