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Targeting YAP1\/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1\/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1\/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1\/TAZ\u2010TEAD transcriptional activity in cells. Among 29\u00a0049 low\u2010molecular\u2010weight compounds screened, we obtained nine hits, and the four of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS\u2010induced LATS kinase activities and thus YAP1\/TAZ phosphorylation. Phosphorylated YAP1\/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT\u2010treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS\u2010YAP pathway driving tumor cell growth and so could be a potent anticancer drug.<\/jats:p>","DOI":"10.1111\/cas.15079","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T18:00:21Z","timestamp":1626890421000},"page":"4303-4316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Alantolactone is a natural product that potently inhibits YAP1\/TAZ through promotion of reactive oxygen species accumulation"],"prefix":"10.1111","volume":"112","author":[{"given":"Keisuke","family":"Nakatani","sequence":"first","affiliation":[{"name":"Division of Molecular and Cellular Biology Kobe University Graduate School of Medicine Kobe Japan"},{"name":"Medical Institute of Bioregulation Kyushu University Fukuoka Japan"},{"name":"Bio Science and Engineering Laboratory Research and Development Management Headquarters FujiFilm 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