{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:54:54Z","timestamp":1794048894731,"version":"4.8.0"},"reference-count":84,"publisher":"European Respiratory Society (ERS)","issue":"177","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir Rev"],"accepted":{"date-parts":[[2025,6,11]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:p>Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease primarily affecting women, manifested as cystic lung destruction, angiomyolipomas (AMLs) and lymphagioleiomyomas. The hallmark of LAM is the presence of abnormal perivascular epithelioid cells, referred to as LAM cells. LAM is classified into tuberous sclerosis-associated (TSC) and sporadic forms according to the presence or absence of TSC gene mutations. In recent decades, the benefit of mechanistic target of rapamycin (mTOR) inhibitors has been demonstrated in stabilising respiratory function, reducing AMLs, lymphangioleiomyoma and chylous effusions, and controlling TSC-associated seizures. In addition to mTOR inhibition, clinical trials have explored therapies targeting autophagy, receptors of tyrosine kinases (RTKs), nonreceptor tyrosine kinases (non-RTKs) and hormones. More recently, new treatments avenues involving immune microenvironment, histamine signalling and Src kinase inhibition have entered pre-clinical and\/or clinical evaluation. This review summarises the multiple pathophysiological mechanisms in LAM and highlights the therapeutic targets identified to date. Several clinical trials have been described, offering insights into their potential application and further research.<\/jats:p>","DOI":"10.1183\/16000617.0019-2025","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T08:46:26Z","timestamp":1754469986000},"page":"250019","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel treatment strategies for lymphangioleiomyomatosis: a narrative review"],"prefix":"10.1183","volume":"34","author":[{"given":"Davide","family":"Elia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8629-7391","authenticated-orcid":false,"given":"Sergio","family":"Harari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9mi","family":"Diesler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth P.","family":"Henske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"2025090301551289000_34.177.250019.1","unstructured":"Fletcher CD , Unni KK , Epstein J . Pathology and Genetics of Tumours of Soft Tissue and Bone. Geneva, World Health Organization International Agency for Research on Cancer, 2002."},{"key":"2025090301551289000_34.177.250019.2","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0163-2019"},{"key":"2025090301551289000_34.177.250019.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200208-969OC"},{"key":"2025090301551289000_34.177.250019.4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201205-0848OE"},{"key":"2025090301551289000_34.177.250019.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.35"},{"key":"2025090301551289000_34.177.250019.6","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.163.1.2005004"},{"key":"2025090301551289000_34.177.250019.7","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/S2213-2600(21)00228-9","article-title":"Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management","volume":"9","author":"McCarthy","year":"2021","journal-title":"Lancet Respir Med"},{"key":"2025090301551289000_34.177.250019.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.11.6085"},{"key":"2025090301551289000_34.177.250019.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc0707517"},{"key":"2025090301551289000_34.177.250019.10","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1165\/rcmb.2023-0243LE","article-title":"Identification of lymphangioleiomyomatosis-associated serum microRNAs","volume":"70","author":"Rossi","year":"2024","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2025090301551289000_34.177.250019.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1100391"},{"key":"2025090301551289000_34.177.250019.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063564"},{"key":"2025090301551289000_34.177.250019.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00220-X"},{"key":"2025090301551289000_34.177.250019.14","doi-asserted-by":"publisher","DOI":"10.1038\/ncb995"},{"key":"2025090301551289000_34.177.250019.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.06.009"},{"key":"2025090301551289000_34.177.250019.16","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.164"},{"key":"2025090301551289000_34.177.250019.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.09.013"},{"key":"2025090301551289000_34.177.250019.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.092353"},{"key":"2025090301551289000_34.177.250019.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15156-5"},{"key":"2025090301551289000_34.177.250019.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.06.054"},{"key":"2025090301551289000_34.177.250019.21","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01061-10"},{"key":"2025090301551289000_34.177.250019.22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131080"},{"key":"2025090301551289000_34.177.250019.23","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0489"},{"key":"2025090301551289000_34.177.250019.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2017.02.012"},{"key":"2025090301551289000_34.177.250019.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.10.029"},{"key":"2025090301551289000_34.177.250019.26","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.179"},{"key":"2025090301551289000_34.177.250019.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44229-4"},{"key":"2025090301551289000_34.177.250019.28","first-page":"347","article-title":"The spectrum of renal \u201cTFEopathies\u201d: flipping the mTOR switch in renal tumorigenesis","volume":"39","author":"Alesi","year":"2024","journal-title":"Physiology (Bethesda)"},{"key":"2025090301551289000_34.177.250019.29","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19030880"},{"key":"2025090301551289000_34.177.250019.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34617-7"},{"key":"2025090301551289000_34.177.250019.31","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-154-12-201106210-00007"},{"key":"2025090301551289000_34.177.250019.32","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1016\/j.chest.2016.02.654","article-title":"Sirolimus therapy for patients with lymphangioleiomyomatosis leads to loss of chylous ascites and circulating LAM cells","volume":"150","author":"Harari","year":"2016","journal-title":"Chest"},{"key":"2025090301551289000_34.177.250019.33","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00210714"},{"key":"2025090301551289000_34.177.250019.34","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61767-X"},{"key":"2025090301551289000_34.177.250019.35","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201607-1384ST"},{"key":"2025090301551289000_34.177.250019.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00757-5"},{"key":"2025090301551289000_34.177.250019.37","doi-asserted-by":"crossref","first-page":"102428","DOI":"10.1016\/j.arr.2024.102428","article-title":"Autophagy in aging-related diseases and cancer: principles, regulatory mechanisms and therapeutic potential","volume":"100","author":"Wu","year":"2024","journal-title":"Ageing Res Rev"},{"key":"2025090301551289000_34.177.250019.38","doi-asserted-by":"publisher","DOI":"10.1038\/nature09127"},{"key":"2025090301551289000_34.177.250019.39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1193497"},{"key":"2025090301551289000_34.177.250019.40","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2247300"},{"key":"2025090301551289000_34.177.250019.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168472"},{"key":"2025090301551289000_34.177.250019.42","doi-asserted-by":"publisher","DOI":"10.4161\/auto.19653"},{"key":"2025090301551289000_34.177.250019.43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1104361108"},{"key":"2025090301551289000_34.177.250019.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2009.06.063"},{"key":"2025090301551289000_34.177.250019.45","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.chest.2017.01.033","article-title":"Sirolimus and autophagy inhibition in lymphangioleiomyomatosis: results of a phase I clinical trial","volume":"151","author":"El-Chemaly","year":"2017","journal-title":"Chest"},{"key":"2025090301551289000_34.177.250019.46","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/nyas.12829","article-title":"Resveratrol as a novel treatment for diseases with mTOR pathway hyperactivation","volume":"1348","author":"Alayev","year":"2015","journal-title":"Ann NY Acad Sci"},{"key":"2025090301551289000_34.177.250019.47","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3537"},{"key":"2025090301551289000_34.177.250019.48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.169284"},{"key":"2025090301551289000_34.177.250019.49","doi-asserted-by":"publisher","DOI":"10.4161\/cc.27355"},{"key":"2025090301551289000_34.177.250019.50","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1165\/rcmb.2015-0022OC","article-title":"Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors","volume":"53","author":"Alayev","year":"2015","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2025090301551289000_34.177.250019.51","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.chest.2023.01.007","article-title":"Safety and efficacy of combined resveratrol and sirolimus in lymphangioleiomyomatosis","volume":"163","author":"Gupta","year":"2023","journal-title":"Chest"},{"key":"2025090301551289000_34.177.250019.52","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2006.071811"},{"key":"2025090301551289000_34.177.250019.53","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00262.2015"},{"key":"2025090301551289000_34.177.250019.54","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)61198-4"},{"key":"2025090301551289000_34.177.250019.55","doi-asserted-by":"crossref","first-page":"315240","DOI":"10.1155\/2015\/315240","article-title":"Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis","volume":"2015","author":"Lesma","year":"2015","journal-title":"Biomed Res Int"},{"key":"2025090301551289000_34.177.250019.56","doi-asserted-by":"publisher","DOI":"10.1038\/84635"},{"key":"2025090301551289000_34.177.250019.57","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402584"},{"key":"2025090301551289000_34.177.250019.58","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908681"},{"key":"2025090301551289000_34.177.250019.59","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/S2213-2600(24)00217-0","article-title":"Nintedanib for patients with lymphangioleiomyomatosis: a phase 2, open-label, single-arm study","volume":"12","author":"Harari","year":"2024","journal-title":"Lancet Respir Med"},{"key":"2025090301551289000_34.177.250019.60","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00204.2003"},{"key":"2025090301551289000_34.177.250019.61","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1895"},{"key":"2025090301551289000_34.177.250019.62","doi-asserted-by":"publisher","DOI":"10.1378\/chest.117.1.25"},{"key":"2025090301551289000_34.177.250019.63","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.160.2.9901027"},{"key":"2025090301551289000_34.177.250019.64","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1513\/AnnalsATS.201610-824OC","article-title":"A phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis","volume":"14","author":"Lu","year":"2017","journal-title":"Ann Am Thorac Soc"},{"key":"2025090301551289000_34.177.250019.65","doi-asserted-by":"publisher","DOI":"10.1378\/chest.07-2277"},{"key":"2025090301551289000_34.177.250019.66","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.chest.2023.02.026","article-title":"Determinants of progression and mortality in lymphangioleiomyomatosis","volume":"164","author":"Xu","year":"2023","journal-title":"Chest"},{"key":"2025090301551289000_34.177.250019.67","doi-asserted-by":"crossref","first-page":"1079317","DOI":"10.3389\/fmed.2023.1079317","article-title":"Lymphangioleiomyomatosis: searching for potential biomarkers","volume":"10","author":"Revilla-Lopez","year":"2023","journal-title":"Front Med (Lausanne)"},{"key":"2025090301551289000_34.177.250019.68","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/17476348.2018.1409622","article-title":"Emerging biomarkers of lymphangioleiomyomatosis","volume":"12","author":"Nijmeh","year":"2018","journal-title":"Expert Rev Respir Med"},{"key":"2025090301551289000_34.177.250019.69","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1186\/s13023-024-03455-9","article-title":"The development for emerging biomarkers of lymphangioleiomyomatosis","volume":"19","author":"Huang","year":"2024","journal-title":"Orphanet J Rare Dis"},{"key":"2025090301551289000_34.177.250019.70","doi-asserted-by":"crossref","first-page":"e230312","DOI":"10.1530\/ERC-23-0312","article-title":"Glycoprotein non-metastatic melanoma protein B promotes tumor growth and is a biomarker for lymphangioleiomyomatosis","volume":"31","author":"Gibbons","year":"2024","journal-title":"Endocr Relat Cancer"},{"key":"2025090301551289000_34.177.250019.71","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3693"},{"key":"2025090301551289000_34.177.250019.72","doi-asserted-by":"publisher","DOI":"10.1016\/j.resinv.2013.03.002"},{"key":"2025090301551289000_34.177.250019.73","doi-asserted-by":"publisher","DOI":"10.1136\/thorax-2023-221148"},{"key":"2025090301551289000_34.177.250019.74","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1165\/rcmb.2019-0117OC","article-title":"Adoptive T-cell transfer to treat lymphangioleiomyomatosis","volume":"62","author":"Han","year":"2020","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2025090301551289000_34.177.250019.75","doi-asserted-by":"crossref","first-page":"e98674","DOI":"10.1172\/jci.insight.98674","article-title":"TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti-PD-1\/anti-CTLA-4 immunotherapy","volume":"3","author":"Liu","year":"2018","journal-title":"JCI Insight"},{"key":"2025090301551289000_34.177.250019.76","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2018-0123OC"},{"key":"2025090301551289000_34.177.250019.77","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41467-023-36881-7","article-title":"mTORC1 upregulates B7-H3\/CD276 to inhibit antitumor T cells and drive tumor immune evasion","volume":"14","author":"Liu","year":"2023","journal-title":"Nat Commun"},{"key":"2025090301551289000_34.177.250019.78","doi-asserted-by":"crossref","first-page":"e152014","DOI":"10.1172\/jci.insight.152014","article-title":"Benign tumors in TSC are amenable to treatment by GD3 CAR T cells in mice","volume":"6","author":"Thomas","year":"2021","journal-title":"JCI Insight"},{"key":"2025090301551289000_34.177.250019.79","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1165\/rcmb.2023-0410OC","article-title":"Plasmacytoid dendritic cells mediate CpG-ODN-induced increase in survival in a mouse model of lymphangioleiomyomatosis","volume":"71","author":"Amosu","year":"2024","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2025090301551289000_34.177.250019.80","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32673-7"},{"key":"2025090301551289000_34.177.250019.81","doi-asserted-by":"crossref","first-page":"e13929","DOI":"10.15252\/emmm.202113929","article-title":"Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis","volume":"13","author":"Herranz","year":"2021","journal-title":"EMBO Mol Med"},{"key":"2025090301551289000_34.177.250019.82","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2004.09.001"},{"key":"2025090301551289000_34.177.250019.83","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1256"},{"key":"2025090301551289000_34.177.250019.84","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2386"}],"container-title":["European Respiratory Review"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/16000617.0019-2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T08:55:33Z","timestamp":1756889733000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/16000617.0019-2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":84,"journal-issue":{"issue":"177","published-online":{"date-parts":[[2025,8,6]]},"published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1183\/16000617.0019-2025"],"URL":"https:\/\/doi.org\/10.1183\/16000617.0019-2025","relation":{},"ISSN":["0905-9180","1600-0617"],"issn-type":[{"value":"0905-9180","type":"print"},{"value":"1600-0617","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]}}}