{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T18:05:32Z","timestamp":1786125932153,"version":"build-2736575974"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ujian Province Young Scientific and Technological Talents Development Program","award":["2025350235"],"award-info":[{"award-number":["2025350235"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by persistent alveolar epithelial injury and aberrant tissue remodeling. Increasing evidence suggests that senescence of alveolar epithelial cells (AECs) contributes to impaired epithelial regeneration and maladaptive tissue repair by limiting reparative capacity and promoting profibrotic signaling. However, the molecular drivers of AEC senescence and their impact on the immune microenvironment in IPF remain incompletely understood. Here, we investigated senescence-associated genes involved in IPF pathogenesis and evaluated their diagnostic and therapeutic potential. IPF transcriptomic datasets were retrieved from the Gene Expression Omnibus (GEO). Senescence-related differentially expressed genes (SRDEGs) were identified by intersecting IPF-derived differentially expressed genes with a curated human senescence gene list. Functional enrichment analyses were performed to delineate SRDEG-associated biological processes. Hub genes were prioritized using machine-learning approaches, and a diagnostic model was constructed and assessed by receiver operating characteristic (ROC) analysis. Candidate genes were further validated through in vivo and in vitro experiments. Given the upstream regulatory role of CHEK2 in DNA damage response-associated cellular senescence, Fostamatinib was screened as a potential therapeutic agent, and its interaction with CHEK2 and functional effects were examined using molecular docking, molecular dynamics simulations, and experimental assays. Two senescence-associated hub genes, CHEK2 and TP53 BP1, were identified as key contributors to IPF pathology (FDR-adjusted P\u2009&lt;\u20090.05), and a model incorporating both genes achieved high diagnostic performance. Experimental validation, however, indicated that only CHEK2 showed IPF-specific differential expression and was closely associated with AEC senescence and fibrotic progression. In silico analyses supported stable binding between Fostamatinib and CHEK2, and subsequent molecular and cellular experiments suggested that Fostamatinib may attenuate CHEK2-associated senescence and profibrotic responses. Collectively, these findings identify CHEK2 as a critical regulator of AEC senescence and IPF development, supporting its potential use as a diagnostic biomarker and therapeutic target. Fostamatinib may represent a candidate therapeutic strategy for IPF by modulating CHEK2-related senescence pathways.<\/jats:p>","DOI":"10.1371\/journal.pone.0353694","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:27:47Z","timestamp":1786123667000},"page":"e0353694","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of senescence-related genes in diagnosing idiopathic pulmonary fibrosis via integrating bioinformatics analysis and machine 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