{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:53:15Z","timestamp":1779205995452,"version":"3.51.4"},"reference-count":65,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Anhui Education Department","award":["2022AH051340"],"award-info":[{"award-number":["2022AH051340"]}]},{"name":"Natural Science Foundation of Anhui Education Department","award":["2022AH051331"],"award-info":[{"award-number":["2022AH051331"]}]},{"name":"Foundation of Fuyang Normal University","award":["2024xqhz051"],"award-info":[{"award-number":["2024xqhz051"]}]},{"name":"Foundation of Fuyang Normal University","award":["2024FYNUFN12"],"award-info":[{"award-number":["2024FYNUFN12"]}]},{"name":"Foundation of Fuyang Normal University","award":["2021KYQD0027"],"award-info":[{"award-number":["2021KYQD0027"]}]},{"name":"Hefei Technology College horizontal project","award":["2024HXKT012"],"award-info":[{"award-number":["2024HXKT012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cathepsin C (CTSC) mediates neutrophil serine protease (NSP) maturation, contributing to inflammatory cascades, making it a key therapeutic target. In this study, through large-scale screening of a natural product library, marrubiin, a diterpenoid lactone compound, was identified as a potent CTSC inhibitor, which holds potential value in the treatment of inflammatory diseases. It inhibited human recombinant CTSC (IC50 = 57.5 nM) and intracellular CTSC (IC50 = 51.6 nM) with acceptable cytotoxicity, and reduced the activity and protein levels of downstream NSPs in vitro. Functionally, marrubiin inhibited lipopolysaccharide-induced nitric oxide release and regulated the levels of cytokines and chemokines. Docking result predicted marrubiin may achieve CTSC activity inhibition by using lactone structure as a covalent unit to target Cys234. In vivo study indicated that high-dose marrubiin (IC50 = 30 mg\/kg) reduced CTSC and NSPs activities in blood and bone marrow in mice without toxicity, and its efficacy was comparable to that of positive compound AZD7986. In the adjuvant-induced arthritis model, high-dose marrubiin (IC50 = 60 mg\/kg) exerted a therapeutic effect by reducing the activities of CTSC and NSPs. These findings indicated marrubiin is a promising natural CTSC inhibitor, which can be used for the treatment of neutrophil-related inflammatory diseases.<\/jats:p>","DOI":"10.3390\/molecules30214170","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T01:35:11Z","timestamp":1761269711000},"page":"4170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Marrubiin as a Cathepsin C Inhibitor for Treating Rheumatoid Arthritis"],"prefix":"10.3390","volume":"30","author":[{"given":"Fei-Long","family":"Zhou","sequence":"first","affiliation":[{"name":"Medical School, Fuyang Normal University, Fuyang 236037, China"},{"name":"Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cui","family":"Chang","sequence":"additional","affiliation":[{"name":"Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da-Xing","family":"Shi","sequence":"additional","affiliation":[{"name":"Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Chen","sequence":"additional","affiliation":[{"name":"Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-Hua","family":"Liu","sequence":"additional","affiliation":[{"name":"Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Bao","family":"Shen","sequence":"additional","affiliation":[{"name":"Medical School, Fuyang Normal University, Fuyang 236037, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113818","DOI":"10.1016\/j.ejmech.2021.113818","article-title":"Cathepsin C inhibitors as anti-inflammatory drug discovery: Challenges and opportunities","volume":"225","author":"Shen","year":"2021","journal-title":"Eur. 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