Natural Products to Overcome Targeted Therapy Resistance in Acute Myeloid Leukemia: Mechanisms, Molecular Targets, and Translational Opportunities

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid cells and remains associated with poor clinical outcomes despite recent therapeutic advances. The introduction of the BCL-2 inhibitor venetoclax has significantly improved response rates, particularly in combination with hypomethylating agents, yet primary and acquired resistance frequently limits durable remission. Mechanisms underlying resistance include apoptotic rewiring; overexpression of MCL-1 and BCL-XL; activation of PI3K/AKT/mTOR, MAPK, NF-κB, and STAT3 signaling; metabolic reprogramming; leukemia stem-cell persistence; epigenetic dysregulation; and protective interactions within the bone marrow microenvironment. Natural products represent a promising source of multitarget therapeutic agents capable of modulating diverse oncogenic networks involved in AML progression and drug resistance. This review comprehensively summarizes the antileukemic potential of phytochemicals including curcumin, parthenolide, resveratrol, quercetin, honokiol, matrine, wogonin, withanolides, homoharringtonine, avocatin B, ajoene, and apigenin. Particular emphasis is placed on their ability to induce apoptosis, eradicate leukemia stem cells, suppress metabolic adaptations, trigger ferroptosis, reverse epigenetic abnormalities, and remodel the tumor microenvironment. We critically evaluate the evidence supporting these mechanisms and discuss translational opportunities, combination strategies, formulation advances, and current challenges related to bioavailability, pharmacokinetics, and biomarker-guided patient selection. We propose that natural products, when integrated into precision medicine frameworks and advanced delivery systems, offer substantial potential as adjunctive therapies for overcoming venetoclax resistance. However, successful clinical translation requires rigorous pharmacokinetic optimization, biomarker-guided patient stratification, and well-designed clinical trials.