biostudies-literatureHan YScience and Technology Department of Zhejiang ProvinceNational Natural Science Foundation of China (National Science Foundation of China)10451https://www.ebi.ac.uk/biostudies/studies/S-EPMC12647908biostudies-literatureUnknown16(1)Eosinophils are the predominant immune cells implicated in the pathogenesis of asthma, highlighting the need for strategies to mitigate their effects. While previous studies have implicated the importance of lysosomes in eosinophil function, the precise role of lysosomes in eosinophil activation during asthma remains insufficiently understood. In this study, we demonstrate that lysosomal acidity and cathepsin L activity in eosinophils are elevated in asthmatic patients and mouse models. Genetic deletion or pharmacological inhibition of cathepsin L in eosinophils attenuates allergic airway inflammation in vivo and suppresses eosinophil activation in vitro. Cathepsin L in eosinophils promotes type 2 immune responses by upregulating arginase 1 expression and interacting with it, thereby enhanNature communicationsLysosomal acidity and cathepsin L activate eosinophils via ARG1-mediated arginine metabolism in allergic airway inflammation.PMC1264790882270023U22A20265822000262023C0306782370027Weng QChen KHua WYing SLv BShen DDong LHan YZhang MJin ZZhao YLi NLi WLiu ZChen ZChen XWang YGao SWu YLou JYan FfalseLysosomal acidity and cathepsin L activate eosinophils via ARG1-mediated arginine metabolism in allergic airway inflammation.Eosinophils are the predominant immune cells implicated in the pathogenesis of asthma, highlighting the need for strategies to mitigate their effects. While previous studies have implicated the importance of lysosomes in eosinophil function, the precise role of lysosomes in eosinophil activation during asthma remains insufficiently understood. In this study, we demonstrate that lysosomal acidity and cathepsin L activity in eosinophils are elevated in asthmatic patients and mouse models. Genetic deletion or pharmacological inhibition of cathepsin L in eosinophils attenuates allergic airway inflammation in vivo and suppresses eosinophil activation in vitro. Cathepsin L in eosinophils promotes type 2 immune responses by upregulating arginase 1 expression and interacting with it, thereby enhan2025-01-01T00:00:00Z2025 Nov2026-06-05T16:48:16.617Z2026-05-18T03:13:30.54ZS-EPMC126479084129059810.1038/s41467-025-65400-z