Abstract
This review critically examines the complex mechanisms underlying venetoclax resistance in acute myeloid leukemia (AML) and explores the therapeutic potential of phytochemicals in overcoming this resistance. Emerging evidence suggests that resistance to venetoclax arises through multiple pathways, including the overexpression of anti-apoptotic proteins, such as MCL1 and BCL2L1, mitochondrial adaptations, metabolic rewiring, and genetic mutations in key regulators, such as TP53 and KMT2A. Phytochemicals, including curcumin, quercetin, triptolide, and parthenolide, have demonstrated anti-leukemic and chemosensitizing activities by modulating BCL2 family proteins and associated apoptotic pathways. Furthermore, in silico docking analyses indicated that several terpenoids possess strong binding affinities to BCL2 protein, in some cases outperforming venetoclax, highlighting their potential as alternative or complementary agents. Preclinical studies underscore the ability of phytochemicals to synergize with venetoclax, enhancing apoptosis and reducing leukemic burden while exhibiting minimal toxicity to normal hematopoietic cells. These bioactive compounds exert pleiotropic effects by modulating redox homeostasis, microRNA expression, epigenetic remodelling, and mitochondrial function, offering a multi-targeted approach to overcoming drug resistance. Despite their promise, translational challenges persist, notably poor solubility, limited bioavailability, and insufficient clinical validation of these compounds. Future research should prioritize the development of advanced delivery systems, such as nanoparticle formulations, and initiate well-designed clinical trials to evaluate the safety, pharmacokinetics, and efficacy of phytochemical-venetoclax combinations in AML.