*Computer-assisted molecular modeling, *Pharmacology, *Protein kinases, *Autophagy, *Research funding, *Flavonoids, *Pharmaceutical chemistry, *Cell proliferation, *Apoptosis, *Protein-tyrosine kinase inhibitors, *Cellular signal transduction, *Cell lines, *Cell receptors, *Drug synergism, *Drug tolerance

Xanthohumol (XN) is an isoprene chalcone found in hops (Humulus lupulus L.), a food ingredient with a wide range of pharmacological activities. The aim of this study was to reveal the therapeutic effect of XN on acute myeloid leukemia (AML) and the potential underlying molecular mechanism. Through network pharmacology analysis, molecular docking, and HTRF determination, XN was shown to inhibit the kinase activities of FLT3 and SRPK1 by targeting their ATPbinding domains, with IC50 values of 1.51 ± 0.44 mM and 0.37 ± 0.15 mM, respectively. By inhibiting AML cell proliferation, promoting apoptosis, regulating autophagy, and inhibiting invasion, XN, which targets the unique FLT3/SRPK1 signaling pathway, exerts anti-AML effects. XN also significantly inhibited FLT3 inhibitor-resistant AML cells and exhibited synergistic interactions with gilteritinib. Moreover, XN at 40 mg/kg effectively inhibited the growth of AML subcutaneous tumors with good tolerance. These results suggest that XN could be a promising therapeutic agent for AML treatment. XN effectively targets the FLT3/SRPK1 signaling axis, demonstrating strong anti-AML effects and offering a potent strategy to address AML. [ABSTRACT FROM AUTHOR]

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