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However, there is a lack of effective drugs for treating non\u2010M3 AML. V8, a newly synthesized derivative of the natural flavonoid wogonin, which is a potential anticancer drug, has demonstrated significant antitumor activity both in\u00a0vitro and in\u00a0vivo. Here, we investigated the effects of V8 on AML cell lines and primary AML cells as well as its underlying mechanisms. Our results showed that V8 exerted significant concentration\u2010dependent growth inhibition and apoptosis induction in AML cells, accompanied by characteristic pathological features including lysosomal functions suppression, mitochondrial dysfunction, and endoplasmic reticulum stress (ERS) activation. Mechanistic investigations revealed that V8 induced mitochondrial membrane potential collapse through elevation of intracellular reactive oxygen species (ROS) levels, while concurrently blocking mitophagy via lysosomal functional inhibition. Furthermore, V8 selectively activated the PERK\/p\u2010eIF2\u03b1\/ATF4 and IRE1\u03b1\/XBP1 signaling axes of ERS, ultimately triggering CHOP\u2010mediated apoptosis through the ERS\u2010specific pathway. In\u00a0vivo studies confirmed that V8 treatment significantly prolonged survival duration in NOD\/SCID mice bearing primary AML xenografts and suppressed tumor progression in BALB\/c nude mice with U937 cell xenografts, with antitumor efficacy closely associated with CHOP\u2010dependent ERS pathway modulation. These findings not only elucidate the multi\u2010targeted mechanism of V8 against AML through coordinated regulation of the ROS\u2010mitochondria\u2010lysosome\u2010ERS signaling network, but also provide critical theoretical foundations for developing natural product\u2010based therapeutics for AML. The multi\u2010pathway synergistic characteristics exhibited by V8 underscore its considerable potential as a clinically translatable candidate drug.<\/jats:p>","DOI":"10.1096\/fj.202500599r","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T07:00:37Z","timestamp":1746860437000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Therapeutic Effect of\n                    <scp>V8<\/scp>\n                    Affecting Mitophagy and Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Mediated by\n                    <scp>ROS<\/scp>\n                    and\n                    <scp>CHOP<\/scp>\n                    Signaling"],"prefix":"10.1096","volume":"39","author":[{"given":"Yong\u2010jian","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention China Pharmaceutical University  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