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Concurrently, bacterial proteases from pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus contribute to immune evasion and tissue destruction, compounding disease severity. Despite advances in antimicrobial and anti-inflammatory therapies, protease-driven lung damage remains a critical challenge. This review examines the dual role of host and bacterial proteases in CF pathophysiology, highlighting emerging protease-targeted therapies aimed at mitigating lung damage and inflammation. Strategies explored include the inhibition of NE, MMPs, and bacterial proteases, with a focus on innovative therapeutic approaches such as dual-function inhibitors, biologics, and advanced drug delivery systems. By restoring the protease\u2013antiprotease balance, these interventions offer the potential to improve clinical outcomes and quality of life for CF patients.<\/jats:p>","DOI":"10.3390\/ijms26051871","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:08:50Z","timestamp":1740136130000},"page":"1871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring Proteases as Alternative Molecular Targets to Tackle Inflammation in Cystic Fibrosis Respiratory Infections"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5107-0960","authenticated-orcid":false,"given":"Angela","family":"Sandri","sequence":"first","affiliation":[{"name":"Department of Diagnostics and Public Health, University of Verona, Strada Le Grazie 8-15, 37134 Verona, Italy"},{"name":"General and Upper GI Surgery Division, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Stefani 1, 37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9623-6859","authenticated-orcid":false,"given":"Federico","family":"Boschi","sequence":"additional","affiliation":[{"name":"Department of Engineering for Innovation Medicine, University of Verona, Strada Le Grazie 8-15, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/ppul.24246","article-title":"Airway microenvironment alterations and pathogen growth in cystic fibrosis","volume":"54","author":"Rossi","year":"2019","journal-title":"Pediatr. 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