1, 8-Cineole Ameliorated <i>Staphylococcus aureus</i>-Induced Pneumonia through Modulation of TRP-KYN and Arginine-NO Reprogramming

1, 8-Cineole (Cin), a cyclic monoterpenoid derived from tea trees and eucalyptus species, exhibits diverse pharmacological properties. Yet, its therapeutic impact and underlying mechanism against <i>Staphylococcus aureus</i> (<i>S. aureus</i>) pneumonia remain to be elucidated. In this study, metabolomics based on UPLC-MS/MS was integrated with network pharmacology, molecular biology, and molecular docking to investigate the effects of Cin. The findings demonstrated that Cin markedly reduced mortality and lung bacterial load, lessened pulmonary damage while suppressing the levels of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the bronchoalveolar lavage fluid (BALF) of infected mice. Additionally, 19 metabolites, primarily involved in tryptophan metabolism and arginine biosynthesis, were notably modified by Cin via suppressing the enzymatic activity of indoleamine 2, 3-dioxygenase 1 (IDO1) and inducible nitric oxide synthase (iNOS), thereby attenuating the inflammatory response. Notably, knockdown of IDO1 or iNOS significantly diminished the anti-inflammation effect of Cin. In conclusion, our study validates the therapeutic potential of Cin against <i>S. aureus</i> pneumonia via anti-inflammation by downregulating IDO1 and iNOS. Our results provide a theoretical basis of natural substances applied in bacterial pneumonia treatment.