Melatonin attenuates Mycoplasma pneumoniae-Induced Inflammation and barrier dysfunction by CXCL10/TLR4/STAT1 axis

Mycoplasma pneumoniae (Mp) is a major pathogen of community-acquired pneumonia increasingly resistant to macrolides. Mp infection provokes oxidative stress, disrupts epithelial integrity, and skews T helper (Th) cell balance through CARDS toxin-mediated immune dysregulation. Here, we investigated the protective effects of melatonin, a pleiotropic hormone with antioxidant and immunomodulatory functions, in patients and a murine model of Mp pneumonia. Mp infection perturbed the local Th1/Th2/Th17 balance, accompanied by ROS accumulation, CXCL10-induced TLR4/STAT1 activation, and loss of ZO1-dependent tight junctions. Melatonin administration suppressed ROS production, restored epithelial barrier integrity, and rebalanced Th responses within the airway microenvironment. Mechanistically, melatonin inhibited CXCL10-TLR4/STAT1 signaling, with TLR4 residue A366 identified as a key regulatory site. These findings reveal that melatonin alleviates Mp-induced airway injury by maintaining immune and epithelial homeostasis, highlighting its potential as an adjunctive therapy for macrolide-resistant Mp pneumonia.