Stachyose attenuates IL-33-associated pulmonary inflammation and GPX4-related redox imbalance in MPTP-treated mice

Background Parkinson’s disease (PD) involves central neurodegeneration and peripheral dysfunction. Whether interleukin-33 (IL-33)-associated airway inflammatory stress modifies intestinal, pulmonary, and nigrostriatal abnormalities in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and whether stachyose (STA) attenuates them, remains unclear. Methods C57BL/6J mice were assigned to control (Ctrl), Ctrl + IL-33, PD, PD + IL-33, or PD + IL-33 + STA groups. MPTP induced PD-like injury; IL-33 was administered intranasally and STA orally. Behavioral, histological, inflammatory, dopaminergic, tight-junction-associated, and pulmonary glutathione peroxidase 4 (GPX4)-related redox and iron indices were assessed. STA–GPX4 compatibility was explored by docking and 100-ns molecular dynamics simulation. Results MPTP impaired behavior, increased midbrain α-synuclein (α-syn), and reduced tyrosine hydroxylase (TH). IL-33 alone induced pulmonary inflammation without reproducing the parkinsonian phenotype. On the MPTP-treated background, IL-33 increased lung injury, pro-inflammatory cytokines, and ferrous iron while reducing interleukin-10 (IL-10), GPX4, and the ratio of reduced glutathione to oxidized glutathione (GSH/GSSG). Compared with PD + IL-33 mice, STA improved behavior, attenuated colonic and pulmonary injury and cytokine imbalance, partially restored tight-junction-associated transcripts, reduced α-syn, restored TH and GPX4, improved GSH/GSSG, and lowered ferrous iron. Computational analyses predicted polar interactions involving lysine 127 and arginine 152 and supported stability of the complex in silico. Conclusion Compared with Ctrl + IL-33 mice, PD + IL-33 mice showed greater pulmonary inflammation and GPX4-related redox and iron disturbances. STA partially alleviated abnormalities under the combined challenge. These findings do not establish causal inter-organ communication, ferroptotic cell death, microbiota dependence, or direct STA–GPX4 target engagement.