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Consequently, there is an urgent need to develop safer and more efficacious treatments for AML. In this study, we examined the effects of 20(S)-protopanaxadiol (20(S)-PPD) on AML cells. Our findings indicate that 20(S)-PPD inhibits cell proliferation and induces apoptosis in AML cells. Mechanistically, 20(S)-PPD-induced apoptosis was at least partially dependent on the anti-apoptotic proteins MCL-1 and Bcl-X<jats:sub>L<\/jats:sub>. Moreover, the downregulation of MCL-1 and Bcl-X<jats:sub>L<\/jats:sub> by 20(S)-PPD is mediated through the inhibition of transcription and a decrease in protein stability. Additionally, results from virtual molecular docking demonstrated that 20(S)-PPD exhibits lower binding energies with MCL-1 and Bcl-X<jats:sub>L<\/jats:sub> (\u22127.58 and \u22128.75\u00a0kcal\/mol, respectively), suggesting that 20(S)-PPD may directly interact with these proteins, thereby accelerating their degradation. Finally, 20(S)-PPD has been shown to synergistically enhance the anti-leukemic activity of venetoclax, a selective Bcl-2 inhibitor, in AML cells. The current study suggests that the continued development of 20(S)-PPD as a therapeutic agent for AML would be advantageous.<\/jats:p>","DOI":"10.3389\/fphar.2025.1530270","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T04:10:30Z","timestamp":1745899830000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["20(S)-protopanaxadiol inhibits proliferation and induces apoptosis of acute myeloid leukemia cells via targeting Bcl-XL and MCL-1"],"prefix":"10.3389","volume":"16","author":[{"given":"Meng","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangshuang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanning","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yundong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1038\/sj.leu.2401573","article-title":"Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid","volume":"13","author":"Andreeff","year":"1999","journal-title":"Leukemia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.jsbmb.2015.12.002","article-title":"Calcitriol and 20(S)-protopanaxadiol synergistically inhibit growth and induce apoptosis in human prostate cancer cells","volume":"158","author":"Ben-Eltriki","year":"2016","journal-title":"J. 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