Phytomedicine. 2026 Mar 26;155:158112. doi: 10.1016/j.phymed.2026.158112. Online ahead of print.
ABSTRACT
BACKGROUND: Post-COVID-19, macrolide-resistant Mycoplasma pneumoniae pneumonia (MPP) has surpassed 90% prevalence in East Asia. Modified Ganlu Xiaodu Decoction (MGLXDD), derived from the classic Chinese herbal medicine for against plague Ganlu Xiaodu Decoction, demonstrates beneficial effects in treating MPP, though its therapeutic mechanism remains unclear.
PURPOSE: To explore the potential mechanism of MGLXDD on MPP.
METHODS: MPP mouse model, macrophage (THP-1) and airway barrier cell (A549 and BEAS-2B) co-culture system were established. The effects of MGLXDD on inflammation and airway barrier injury were evaluated using histopathological and immunohistochemical techniques. Transcriptomics and proteomics were performed to screen key targets and pathways of MGLXDD in treating MPP. Bioactive compounds of MGLXDD were identified by mass spectrometry. Molecular docking and surface plasmon resonance (SPR) were employed to evaluate the binding affinity of bioactive compounds to ZBP1, the main sensor of PANoptosis. Using siRNA knockdown, immunofluorescence, electron microscopy, and flow cytometry, the central role of ZBP1-mediated PANoptosis in MPP-related cytokine storm and epithelial barrier injury, and the therapeutic effects of MGLXDD on this process, were verified.
RESULTS: MGLXDD effectively alleviated the severe inflammatory response and airway barrier injury caused by mycoplasma pneumoniae (MP) both in vivo and in vitro. The multi-omics showed that the ZBP1-mediated PANoptosis played a key role in the pathogenesis of MPP, and MGLXDD significantly inhibited this pathway. Mechanistic research verified that MP infection specifically activated ZBP1 in macrophages, triggering a PANoptosis cascade. By reducing ZBP1 expression, activation of key PANoptosis-related molecules, including caspase-1, MLKL, and caspase-3, was effectively inhibited, significantly alleviating inflammation and barrier injury. SPR analysis and both in vitro and in vivo experiments demonstrated that the bioactive components of MGLXDD can directly bind to the ZBP1 protein, suppress PANoptosis by modulating ZBP1 expression, and thereby exert therapeutic effects.
CONCLUSION: ZBP1-mediated PANoptosis is the core pathological mechanism underlying airway barrier injury in MPP. MGLXDD achieves dual anti-inflammatory and airway protective effects by specifically targeting the ZBP1 and inhibiting its mediated PANoptosis, offering a potential therapeutic strategy for drug-resistant MPP.
PMID:41936172 | DOI:10.1016/j.phymed.2026.158112
