Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma

Mitochondrial dysfunction drives persistent inflammation in severe asthma, yet its upstream metabolic regulation remains unclear. Induced sputum from patients with severe asthma was analyzed and integrated with transcriptomic datasets from independent cohorts. Two mouse models (C57BL/6J) were used for in vivo validation with multi-omics profiling, and mechanistic studies were performed in air–liquid interface-cultured primary human airway epithelial cells. Glutathione reduced form (GSHr) was markedly depleted in sputum and associated with poor disease control and mixed granulocytic inflammation in patients with severe asthma. Multi-omics analyses revealed coordinated disruption of glutathione (GSH) metabolism, including oxidized GSH accumulation, reduced synthesis and glutathione-S-transferase activity, and impaired mitochondrial GSH transport. GSH supplementation alleviated airway inflammation, oxidative stress, and mitochondrial dysfunction, whereas pharmacological inhibition of GST exacerbated these effects. Mitochondrial analyses identified suppressed SLC25A39 expression as a key mediator of defective GSH transport and redox imbalance. Transcriptomic profiling of airway biopsies showed upregulation of Neuropilin-1 (Nrp1), closely associated with altered glutathione pathways. Targeting the Nrp1 b1 domain restored mitochondrial GSH metabolism and attenuated airway inflammation. These findings identify an Nrp-centered metabolic pathway that disrupts mitochondrial homeostasis and drives inflammatory amplification, highlighting mitochondria-targeted therapeutic strategies for severe asthma.