{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:06:36Z","timestamp":1787508396829,"version":"build-2736575974"},"reference-count":173,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been extensively employed in identifying drugs that target specific defects arising from CFTR mutations. The two main categories of such compounds are potentiators, which enhance CFTR gating by increasing the channel\u2019s open probability, and correctors, which improve CFTR protein folding and trafficking to the plasma membrane. In addition to these, other investigational molecules include amplifiers and stabilizers, which enhance the levels and the stability of CFTR on the cell surface, and read-through agents that promote the insertion of correct amino acids at premature termination codons. Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445\/VX-661\/VX-770 (marketed as Trikafta\u00ae in the US and Kaftrio\u00ae in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele. Despite these advancements, the mechanisms of action and binding sites of these modulators on CFTR have only recently begun to be elucidated. A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF.<\/jats:p>","DOI":"10.3390\/cimb47020119","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T11:01:08Z","timestamp":1739271668000},"page":"119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review"],"prefix":"10.3390","volume":"47","author":[{"given":"Debora","family":"Baroni","sequence":"first","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche (CNR), Via De Marini, 6, 16149 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1340388","DOI":"10.3389\/fmed.2023.1340388","article-title":"What the future holds: Cystic fibrosis and aging","volume":"10","author":"Blankenship","year":"2024","journal-title":"Front. 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