Histidine metabolic reprogramming drives oxidative stress induced mtDNA release to promote necroptosis and airway inflammation in severe asthma

Metabolic dysregulation is increasingly recognized as a critical contributor to asthma pathogenesis. Emerging clinical and metabolomic evidence has implicated histidine metabolism in asthma; however, whether histidine metabolic reprogramming contributes to severe asthma pathogenesis and the underlying mechanisms remain unclear. Here, we integrated clinical cohort analyses, multi-omics profiling, primary human airway epithelial cell experiments, and both toluene diisocyanate (TDI)- and house dust mite/lipopolysaccharide (HDM/LPS)-induced severe asthma murine models to systematically delineate this relationship. Histidine levels were markedly elevated in induced sputum from asthma patients and were strongly associated with disease severity, airflow limitation, and inflammatory indices. Integrated metabolomic and transcriptomic analyses revealed a pathogenic reprogramming of histidine metabolism, characterized by enhanced histamine biosynthesis and depletion of the cytoprotective carnosine, thereby amplifying airway inflammatory responses. Pharmacological blockade of histidine metabolism significantly alleviated airway hyperresponsiveness, inflammation, and structural remodeling in both TDI- and HDM/LPS-induced severe asthma models. Mechanistically, histidine metabolic dysregulation drives oxidative stress mediated mitochondrial dysfunction, leading to mtDNA release and subsequent activation of mt-ND6/FPR2 signaling, ultimately triggering necroptotic epithelial cell death. Collectively, these findings define a histidine-driven oxidative stress–mtDNA–necroptosis axis as a central mechanism of airway inflammation in severe asthma, offering new therapeutic opportunities through metabolic targeting.