{"doi":"10.1101/2025.05.22.655638","title":"Cellular profiling identifies an early profibrotic alveolar type 2 cell signature in lung fibrosis","abstract":"Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive, age-associated, lung disease characterized by short telomeres in alveolar type 2 (AT2) cells, epithelial remodeling, and fibrosis. Objectives This study investigated how telomere dysfunction in AT2 cells lacking Telomere Repeat Binding Factor 1 (TRF1) drives lung remodeling in SPC-creTRF1 flox/flox mice and its relevance to IPF. Methods Mouse model of telomere dysfunction was used to conditionally delete TRF1 in AT2 cells. SPC-creTRF1 flox/flox mouse lung epithelial cells were used to perform single cell RNA sequencing. AT2 cells from IPF lungs were analyzed by single cell RNA sequencing in an organoid model. Measurements and Main Results Single cell RNA-sequencing revealed distinct pathological AT2 cells enriched in DNA damage, senescence, oxidative stress, and pro-fibrotic genes, along with fewer “normal” AT2 cells and increased club cells in SPC-creTRF1 flox/flox mice. Pathological AT2 cells showed different early and late-stage gene signatures, with a prominent p53 signature at both time-points. Genetic deletion of p53 in SPC-creTRF1 flox/flox AT2 cells improved survival and prevented lung fibrosis. p53 deletion or inhibition improved organoid formation, surfactant protein C expression, and reduced pro-fibrotic gene expression in AT2 cells isolated from SPC-creTRF1 flox/flox mice or IPF lungs. Conclusions These data suggest that the DNA damage response to AT2 cell telomere dysfunction, driven by enhanced p53 activity, mediates early AT2 cell transdifferentiation and senescence, leading to epithelial cell remodeling and fibrosis and that reversing this reprogramming is a potential therapeutic approach for managing IPF.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566675,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1470699,"name":"Alexey V. Bazarov","orcid":"0000-0003-1609-4323","position":1,"is_corresponding":false},{"id":1426899,"name":"Michael Wax","orcid":null,"position":2,"is_corresponding":false},{"id":647264,"name":"Kaveh Boostanpour","orcid":null,"position":3,"is_corresponding":false},{"id":311018,"name":"Jasleen Kukreja","orcid":"0000-0003-2991-6680","position":4,"is_corresponding":false},{"id":55365,"name":"Michela Traglia","orcid":"0000-0002-3361-4602","position":5,"is_corresponding":false},{"id":996227,"name":"Ayushi Agrawal","orcid":"0000-0003-2940-8926","position":6,"is_corresponding":false},{"id":71688,"name":"Reuben Thomas","orcid":"0000-0003-3176-7303","position":7,"is_corresponding":false},{"id":3388,"name":"Mallar Bhattacharya","orcid":"0000-0002-5439-547X","position":8,"is_corresponding":false},{"id":3386,"name":"Paul J. Wolters","orcid":"0000-0002-3108-6164","position":9,"is_corresponding":false},{"id":40357,"name":"Ram P. Naikawadi","orcid":"0000-0001-9061-7044","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:56:40.491968Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}