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Although roflumilast, a selective phosphodiesterase-4 inhibitor, has shown clinical benefits in chronic inflammatory diseases, its potential role in OA has not been defined. Here, we examined whether roflumilast can protect chondrocytes against apoptosis and extracellular matrix (ECM) degradation under inflammatory stress. In IL-1\u03b2\u2013stimulated primary chondrocytes, roflumilast pretreatment (20 \u00b5M) suppressed the expression of matrix-degrading enzymes MMP13 and ADAMTS5, while restoring collagen II and aggrecan, thereby maintaining ECM integrity. Transcriptomic profiling identified a strong upregulation of cystic fibrosis transmembrane conductance regulator (CFTR) alongside the suppression of apoptosis-related genes. Mechanistically, roflumilast activated the Akt\/Bcl-2 signaling cascade, and either pharmacological blockade or siRNA silencing of CFTR abolished these protective effects, indicating a CFTR-dependent pathway. Consistently, human OA cartilage displayed a marked reduction in CFTR expression, underscoring the clinical relevance of this mechanism. In vivo, roflumilast treatment in the destabilization of the medial meniscus mouse model alleviated cartilage erosion, improved subchondral bone architecture, and reduced synovial inflammation. Behavioral and imaging assessments further confirmed enhanced locomotor performance and mitigated joint degeneration. Collectively, our findings identify CFTR as a crucial mediator of roflumilast-induced chondroprotection and highlight roflumilast as a promising candidate for disease modification in OA.<\/jats:p>","DOI":"10.1186\/s13075-026-03872-0","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:29:11Z","timestamp":1784878151000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Roflumilast mitigates cartilage degeneration in osteoarthritis by activating CFTR-mediated anti-apoptotic signaling"],"prefix":"10.1186","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-6065","authenticated-orcid":false,"given":"Haoyu","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4727-5522","authenticated-orcid":false,"given":"Guihua","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4866-4697","authenticated-orcid":false,"given":"Xunhao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6428-8068","authenticated-orcid":false,"given":"Nuo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8035-2650","authenticated-orcid":false,"given":"Wenli","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9370-2649","authenticated-orcid":false,"given":"Ruiyang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3225-3611","authenticated-orcid":false,"given":"Xiaoyu","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4293-7670","authenticated-orcid":false,"given":"Chenfeng","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4327-1356","authenticated-orcid":false,"given":"Zhaofeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1308-4915","authenticated-orcid":false,"given":"Gang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7153-9327","authenticated-orcid":false,"given":"Dongquan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6282-7825","authenticated-orcid":false,"given":"Jingyi","family":"Mi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"issue":"6","key":"3872_CR1","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/s41419-020-2680-0","volume":"11","author":"S Hu","year":"2020","unstructured":"Hu S, Zhang C, Ni L, Huang C, Chen D, Shi K, et al. 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The collection and experimental use of human cartilage specimens were approved by the Ethical Committee of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University (approval no. 2020-156-01), and conducted in accordance with the institutional guidelines and the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dongquan Shi, Guihua Tan, Haoyu Yang, Xunhao Wang, and Nuo Xu are named as inventors on a pending patent application (Application No. 202410809037.2), which is assigned to Nanjing Drum Tower Hospital and is related to the technology described in this manuscript. All other authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"186"}}