{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:06:02Z","timestamp":1785434762958,"version":"3.56.0"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017959","name":"Health Commission of Hebei Province","doi-asserted-by":"publisher","award":["20240572"],"award-info":[{"award-number":["20240572"]}],"id":[{"id":"10.13039\/100017959","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"\n Background<\/jats:title>\n The treatment of non-small cell lung cancer (NSCLC) has challenges such as drug resistance and recurrence. Concurrently, the induction of apoptosis and ferroptosis is a promising therapeutic strategy. This study aimed to investigate whether the natural product, verbascoside, induces apoptosis and ferroptosis in NSCLC cells by targeting BCAT2.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Bioinformatic analysis was used to predict the potential targets of verbascosides. Stable cell lines with BCAT2 knockdown and overexpression were constructed. The effects of verbascoside on NSCLC were evaluated\n in vitro<\/jats:italic>\n and using a mouse xenograft model.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Bioinformatics screening and molecular docking identified BCAT2 as a potential target of verbascoside, with a significantly stronger binding energy (\u22127.8 kcal\/mol) than another candidate, PARP1.\n In vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n experiments confirmed that BCAT2 knockdown significantly inhibited NSCLC cell viability, induced apoptosis and ferroptosis, and induced mitochondrial damage. Conversely, BCAT2 overexpression produced opposite effects. Verbascoside treatment inhibited BCAT2 expression in a concentration-dependent manner, recapitulating the apoptotic, ferroptotic, and mitochondrial damage phenotypes induced by BCAT2 knockdown; however, BCAT2 overexpression significantly reversed these effects of verbascoside. In an animal model, treatment with verbascoside significantly suppressed tumor growth and activated apoptosis and ferroptosis in tumor tissues by downregulating BCAT2.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Verbascoside can induce apoptosis and ferroptosis in NSCLC by directly targeting and inhibiting BCAT2, leading to mitochondrial dysfunction. This finding not only reveals BCAT2 as a novel target of verbascoside but also confirms its ability to induce apoptosis and ferroptosis in NSCLC cells.<\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pone.0354955","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:41:56Z","timestamp":1785433316000},"page":"e0354955","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Verbascoside triggers apoptosis and ferroptosis in NSCLC by targeting 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myocardial ischemia\/reperfusion-induced ferroptosis following heterotopic heart transplantation via modulating GDF15\/GPX4\/SLC7A11 pathway","volume":"15","author":"Y Zhang","year":"2025","journal-title":"Sci Rep"},{"key":"pone.0354955.ref011","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1186\/1471-2407-14-747","article-title":"Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer","volume":"14","author":"L Zhou","year":"2014","journal-title":"BMC Cancer"},{"issue":"12","key":"pone.0354955.ref012","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1038\/s42255-022-00689-4","article-title":"Metabolon formation regulates branched-chain amino acid oxidation and homeostasis","volume":"4","author":"M Patrick","year":"2022","journal-title":"Nat Metab"},{"issue":"7","key":"pone.0354955.ref013","doi-asserted-by":"crossref","first-page":"4022","DOI":"10.3390\/ijms23074022","article-title":"The Critical Role of the Branched Chain Amino 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