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Cathepsins (CTSs), lysosomal proteases that regulate immune processes such as autophagy, antigen presentation, and cytokine modulation, have been implicated in allergy, but whether specific CTSs\u2014particularly cathepsin B (CTSB)\u2014causally contribute to asthma and through which mechanisms remains unclear. Here, we integrated genetic, transcriptomic, and experimental approaches to determine whether CTSB contributes to asthma pathogenesis. Mendelian randomization analyses using large-scale genome-wide association study data revealed that elevated circulating CTSB levels causally increased asthma risk, whereas no causal effects were observed for other allergic diseases. Functional validation in a C57BL\/6 mouse ovalbumin\u2013induced asthma model showed increased pulmonary CTSB expression, and pharmacological inhibition with the broad-spectrum cysteine protease inhibitor E64 or the more selective CTSB inhibitor CA-074Me attenuated airway inflammation and remodeling. Bulk RNA sequencing (RNA-seq) from asthma patients and single-cell RNA-seq (scRNA-seq) datasets identified macrophages as the predominant CTSB-expressing immune cell population, with enrichment of pathways related to apoptosis and autophagy. In vivo, CTSB inhibition reduced lung-tissue autophagy and apoptosis, consistent with macrophages being the dominant CTSB-expressing population in scRNA-seq, suggesting a role for macrophages in these processes. These findings provide genetic and experimental evidence that CTSB promotes asthma pathogenesis and highlight CTSB as a potential therapeutic target for asthma.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag020","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:57:40Z","timestamp":1773827860000},"source":"Crossref","is-referenced-by-count":0,"title":["Cathepsin B promotes asthma potentially via macrophage-associated autophagy and apoptosis"],"prefix":"10.1093","volume":"215","author":[{"given":"Lifen","family":"Gong","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbao","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7913-3372","authenticated-orcid":false,"given":"Hang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"2026052212181180300_vkag020-B1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jaci.2014.08.042","article-title":"The prevalence of severe refractory asthma","volume":"135","author":"Hekking","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"2026052212181180300_vkag020-B2","first-page":"118","article-title":"Understanding the immunology of asthma: 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