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However, a causal role for tDDR in IPF pathogenesis has not been determined. IPF patients frequently bear germline mutations in telomerase genes, critically short telomeres, and markers of tDDR and cellular senescence. We previously demonstrated that telomeric antisense-oligonucleotides (tASOs) targeting telomeric non-coding RNAs are selective tDDR inhibitors. Here, we employed late-generation telomerase knockout mice as a genetic model of IPF. Systemic tASOs treatment reduces DDR\u2014including in stem\/progenitor cells\u2014inflammation, and lung fibrosis in young, adult, and old mice. Markers of DDR correlate with lung pathology, and tDDR inhibition normalizes molecular and pathological phenotypes, uncoupling telomere lengths from their deleterious consequences. Transcriptomic changes in telomerase knockout mice recapitulate those observed in normal aged mice and in IPF patients, and they are reversed upon tDDR inhibition. These results highlight the pathogenic causative relevance of tDDR activation in IPF pathogenesis and support tASOs as a promising therapeutic strategy for IPF and for telomere biology diseases.<\/jats:p>","DOI":"10.1038\/s44321-026-00500-x","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:47:02Z","timestamp":1786528022000},"page":"3704-3744","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The telomeric DNA damage response as a therapeutic target in idiopathic pulmonary fibrosis"],"prefix":"10.1038","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6240-9907","authenticated-orcid":false,"given":"Francesca","family":"Rossiello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4121-5679","authenticated-orcid":false,"given":"Giada","family":"Cicio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-9189","authenticated-orcid":false,"given":"Sara","family":"Sepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-8483","authenticated-orcid":false,"given":"Alexandra","family":"Mancheno-Ferris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Cancila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7410-3231","authenticated-orcid":false,"given":"Arianna","family":"Castellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7944-3143","authenticated-orcid":false,"given":"Federica","family":"Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Bertolazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Oppezzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Marinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Cabrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"di Lillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Tavella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Rosso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca M","family":"Buffa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Tripodo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9603-5966","authenticated-orcid":false,"given":"Fabrizio","family":"d\u2019Adda di Fagagna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"500_CR1","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1038\/ncb2784","volume":"15","author":"JC Acosta","year":"2013","unstructured":"Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. 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