{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:06:34Z","timestamp":1789639594114,"version":"4.0.0"},"reference-count":80,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H02885"],"award-info":[{"award-number":["19H02885"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["19H02885"],"award-info":[{"award-number":["19H02885"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alantolactone is a sesquiterpene lactone that possesses anticancer and anti-inflammatory properties. We previously demonstrated that several sesquiterpenes, including alantolactone, induced the ectodomain shedding of tumor necrosis factor receptor 1 (TNF-R1). In the present study, we investigated the upstream signaling pathway underlying alantolactone-induced TNF-R1 ectodomain shedding. Alantolactone down-regulated the expression of full-length TNF-R1 on the cell surface of human lung adenocarcinoma A549 cells, and this was accompanied by an increase in soluble TNF-R1 in the culture medium. TNF-R1 ectodomain shedding was also detected in human embryonic kidney 293T cells and human fibrosarcoma HT-1080 cells, indicating the conservation of this effect in multiple cell lines. The metalloproteinase inhibitor GM6001 markedly suppressed alantolactone-induced soluble TNF-R1 release and restored cell-surface TNF-R1 expression. Among specific inhibitors targeting mitogen-activated protein kinase (MAPK) signaling pathways, TNF-R1 ectodomain shedding was markedly suppressed by the MAPK\/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, whereas the suppressive effects of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 or the p38 MAPK inhibitor SB203580 were negligible. Consistent with these results, alantolactone increased phospho-ERK and phospho-RAF1 levels within 60\u2013120 min, while p38 MAPK and JNK were minimally phosphorylated during the 120-min incubation. Collectively, these results indicate that alantolactone-induced TNF-R1 ectodomain shedding is mediated by the activation of the RAF1\u2013ERK signaling pathway.<\/jats:p>","DOI":"10.3390\/molecules31183296","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:59:03Z","timestamp":1789639143000},"page":"3296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alantolactone Activates the Extracellular Signal-Regulated Kinase Signaling Pathway to Promote Tumor Necrosis Factor Receptor 1 Ectodomain Shedding"],"prefix":"10.3390","volume":"31","author":[{"given":"Piimwara","family":"Yarangsee","sequence":"first","affiliation":[{"name":"Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Quy Van","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-4022","authenticated-orcid":false,"given":"Yasunobu","family":"Miyake","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6000-4500","authenticated-orcid":false,"given":"Takao","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan"},{"name":"Center for Social and Biomedical Engineering, Kyoto Institute of Technology, Kyoto 606-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chavda, V.P., Feehan, J., and Apostolopoulos, V. 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