{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:31:22Z","timestamp":1789115482489,"version":"build-2803163510"},"reference-count":29,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"unspecified","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","award":["24JRRA923"],"award-info":[{"award-number":["24JRRA923"]}],"id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","award":["25YFFA055"],"award-info":[{"award-number":["25YFFA055"]}],"id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Gansu Provincial Health Industry Scientific Research Project","award":["GSWSKY2025-11"],"award-info":[{"award-number":["GSWSKY2025-11"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260325"],"award-info":[{"award-number":["82260325"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital","award":["CY2023-QN-B06"],"award-info":[{"award-number":["CY2023-QN-B06"]}]},{"name":"Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital","award":["CY2024-MS-A03"],"award-info":[{"award-number":["CY2024-MS-A03"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2026,1,5]]},"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myositis-associated interstitial lung disease (MAILD) is one of the most severe complications of idiopathic inflammatory myopathy, characterised by rapidly progressive pulmonary fibrosis and high mortality. Treatment options are limited, and mechanisms driving epithelial-mesenchymal transition (EMT) in MAILD are incompletely understood. Anlotinib, a multitarget tyrosine kinase inhibitor, shows potential in fibrotic diseases; however, its role and mechanism in MAILD need clarification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To assess anlotinib\u2019s therapeutic effects, we established a MAILD mouse model and a neutrophil extracellular trap (NET)-induced human alveolar epithelial cell (A549) model. H&amp;E and Masson staining analysed lung pathological changes and collagen deposition. Immunohistochemistry, immunofluorescence and Western blot detected expressions of NETs markers (myeloperoxidase, citrullinated histone H3), phosphatidylinositol 3-kinase\/protein kinase B (PI3K)\/Akt components and EMT markers (E-cadherin, \u03b1-smooth muscle actin). RNA sequencing and gene set enrichment analysis identified differentially expressed genes and signalling pathways. Cell counting kit-8 (CCK-8), 5-ethynyl-2\u2032-deoxyuridine (EdU) and wound healing assays assessed cellular repair and migration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MAILD mouse lungs showed structural damage, inflammatory infiltration, collagen deposition, increased NETs formation, PI3K\/Akt activation and enhanced EMT. Anlotinib significantly ameliorated pulmonary fibrosis and reduced pro-inflammatory cytokines (tumour necrosis factor-\u03b1 (TNF-\u03b1), interleukin (IL)-6, IL-1\u03b2). In vivo and in vitro, anlotinib suppressed NETs formation, PI3K\/Akt activation and EMT, while enhancing alveolar epithelial cell repair and migration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Anlotinib alleviates MAILD progression by inhibiting the NETs\u2013PI3K\/Akt axis and subsequent EMT, providing a theoretical basis for drug repurposing and supporting its clinical translation potential in MAILD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2025-006443","type":"journal-article","created":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T19:25:15Z","timestamp":1771183515000},"page":"e006443","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Anlotinib ameliorates myositis-associated interstitial lung disease (MAILD) via suppression of the NETs-PI3K\/Akt-driven epithelial-mesenchymal transition"],"prefix":"10.1136","volume":"12","author":[{"given":"Jumei","family":"Yang","sequence":"first","affiliation":[{"name":"Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chai","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2304-2225","authenticated-orcid":false,"given":"Jiarui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Cui","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyan","family":"Su","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Guo","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyue","family":"Feng","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1565-1431","authenticated-orcid":false,"given":"Sigong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Lanzhou University Second Hospital, Lanzhou, China"},{"name":"Gansu Provincial Clinical Center for Rheumatology and Immunology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,2,15]]},"reference":[{"key":"2026021511250800000_12.1.e006443.1","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00296-023-05336-z","article-title":"Management of myositis associated interstitial lung disease","volume":"43","author":"Thong","year":"2023","journal-title":"Rheumatol Int"},{"key":"2026021511250800000_12.1.e006443.2","first-page":"e70","article-title":"Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases","volume":"95","author":"Allenbach","year":"2020","journal-title":"Neurology (ECronicon)"},{"key":"2026021511250800000_12.1.e006443.3","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/art.42308","article-title":"Identification of Three Different Phenotypes in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis Patients: Implications for Prediction of Rapidly Progressive Interstitial Lung Disease","volume":"75","author":"Xu","year":"2023","journal-title":"Arthritis Rheumatol"},{"key":"2026021511250800000_12.1.e006443.4","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s12016-020-08822-5","article-title":"Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis","volume":"60","author":"Wu","year":"2021","journal-title":"Clin Rev Allergy Immunol"},{"key":"2026021511250800000_12.1.e006443.5","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0133702","article-title":"Efficacy of Rituximab in Refractory Inflammatory Myopathies Associated with Anti- Synthetase Auto-Antibodies: An Open-Label, Phase II Trial","volume":"10","author":"Allenbach","year":"2015","journal-title":"PLoS ONE"},{"key":"2026021511250800000_12.1.e006443.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-016-2464-0"},{"key":"2026021511250800000_12.1.e006443.7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39104"},{"key":"2026021511250800000_12.1.e006443.8","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00163.2007"},{"key":"2026021511250800000_12.1.e006443.9","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-017-3799-y"},{"key":"2026021511250800000_12.1.e006443.10","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/cei.12319","article-title":"Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications","volume":"177","author":"Zhang","year":"2014","journal-title":"Clin Exp Immunol"},{"key":"2026021511250800000_12.1.e006443.11","doi-asserted-by":"crossref","first-page":"867516","DOI":"10.3389\/fimmu.2022.867516","article-title":"Neutrophil Extracellular Traps (NETs) Promote Non-Small Cell Lung Cancer Metastasis by Suppressing lncRNA MIR503HG to Activate the NF-\u03baB\/NLRP3 Inflammasome Pathway","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"2026021511250800000_12.1.e006443.12","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204837"},{"key":"2026021511250800000_12.1.e006443.13","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3758"},{"key":"2026021511250800000_12.1.e006443.14","doi-asserted-by":"crossref","DOI":"10.1038\/s41392-024-02011-y","article-title":"Overexpression of STX11 alleviates pulmonary fibrosis by inhibiting fibroblast activation via the PI3K\/AKT\/mTOR pathway","volume":"9","author":"Huang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"2026021511250800000_12.1.e006443.15","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2008.328"},{"key":"2026021511250800000_12.1.e006443.16","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1001\/jamaoncol.2018.3039","article-title":"Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial","volume":"4","author":"Han","year":"2018","journal-title":"JAMA Oncol"},{"key":"2026021511250800000_12.1.e006443.17","doi-asserted-by":"crossref","first-page":"744826","DOI":"10.3389\/fphar.2021.744826","article-title":"Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis","volume":"12","author":"Chen","year":"2021","journal-title":"Front Pharmacol"},{"key":"2026021511250800000_12.1.e006443.18","doi-asserted-by":"crossref","DOI":"10.1093\/cei\/uxae106","article-title":"A novel mouse model of myositis-associated interstitial lung disease was established by using TLR9 agonist combined with muscle homogenate","volume":"219","author":"Bai","year":"2025","journal-title":"Clin Exp Immunol"},{"key":"2026021511250800000_12.1.e006443.19","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.2147\/DDDT.S426898","article-title":"Research Progress on Mechanism and Management of Adverse Drug Reactions of Anlotinib","volume":"17","author":"Li","year":"2023","journal-title":"Drug Des Devel Ther"},{"key":"2026021511250800000_12.1.e006443.20","doi-asserted-by":"crossref","DOI":"10.1183\/16000617.0004-2022","article-title":"Practical recommendations to combine small-molecule inhibitors and direct oral anticoagulants in patients with nonsmall cell lung cancer","volume":"31","author":"Otten","year":"2022","journal-title":"Eur Respir Rev"},{"key":"2026021511250800000_12.1.e006443.21","doi-asserted-by":"crossref","first-page":"114144","DOI":"10.1016\/j.intimp.2025.114144","article-title":"cGAS-STING mediates neutrophil extracellular traps-induced EMT in myositis-associated interstitial lung disease: STING as a potential therapeutic target","volume":"149","author":"Feng","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"2026021511250800000_12.1.e006443.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2021.06.037"},{"key":"2026021511250800000_12.1.e006443.23","doi-asserted-by":"publisher","DOI":"10.1002\/path.4359"},{"key":"2026021511250800000_12.1.e006443.24","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-020520-111016"},{"key":"2026021511250800000_12.1.e006443.25","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201504-0780OC"},{"key":"2026021511250800000_12.1.e006443.26","first-page":"523","article-title":"Anti-inflammatory and antifibrotic effects of resveratrol in the lung","volume":"30","author":"Conte","year":"2015","journal-title":"Histol Histopathol"},{"key":"2026021511250800000_12.1.e006443.27","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.105"},{"key":"2026021511250800000_12.1.e006443.28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/jphp.13183","article-title":"Anlotinib attenuated bleomycin-induced pulmonary fibrosis via the TGF-\u03b21 signalling pathway","volume":"72","author":"Ruan","year":"2020","journal-title":"J Pharm Pharmacol"},{"key":"2026021511250800000_12.1.e006443.29","doi-asserted-by":"crossref","DOI":"10.1186\/s13046-022-02477-0","article-title":"PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K\/AKT signaling in tumor cells and phenotypic polarization of macrophages","volume":"41","author":"Wang","year":"2022","journal-title":"J Exp Clin Cancer Res"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2025-006443","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T19:25:17Z","timestamp":1771183517000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2025-006443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,2,15]]},"published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1136\/rmdopen-2025-006443"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2025-006443","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]}}}