English: FIGURE 1 (A). When cells are mainly dependent on BCL-2 for survival, apoptosis is effectively mediated by the action of the small-molecule BCL-2-targeted inhibitor venetoclax. BH3-only proteins are bound to antiapoptotic proteins, ensuring the survival of cancer cells, but venetoclax, a BH3-only protein mimetic, displaces the bound BIM from BCL-2. Free BIM activates the free proapoptotic protein BAX/BAK, and activated BAX/BAK oligomerizes on the outer mitochondrial membrane, forming pore channels and releasing cytochrome c located between the inner and outer mitochondrial membranes into the cytoplasm. Cytochrome c activates caspases in the cytoplasm, stimulating the mitochondrial apoptotic pathway and mediating apoptosis. However, if MCL-1 and BCL-XL expression are upregulated (which may be caused by mechanisms shown in Figure 1b. Since, venetoclax, which only targets BCL-2, does not effectively play a role in releasing the BH3-only protein because non-BCL-2 antiapoptotic proteins bind the BH3-only protein at this time, and thus the cell survives and develops venetoclax resistance (Created with BioRender.com). (B). Tumor cells upregulate other antiapoptotic proteins, such as MCL-1 and BCL-XL, through various signaling pathways or other mechanisms to increase their binding to BH3-only proapoptotic factors, such as BIM. Downregulation of the negative regulator PTEN leads to the activation of the AKT pathway, which directly upregulates the expression of BCL-XL and promotes the dissociation of BAD from BCL-XL and binding to 14-3-3 protein by phosphorylating the BAD protein. The NF-κB pathway, which is activated by microenvironmental agonists such as IL-10, CD40, and TLR9 agonists, and the activated PKA-ERK-CREB pathway induce both BCL-XL and MCL-1 expression, and the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways, with the FOXM1-AKT cycle promoting sustained activation of the AKT pathway. By activating NF-κB and ERK pathways, KRAS mutations or wnt5a-ROR1 signaling pathways can cause upregulated expression of MCL-1 or BCL-XL, respectively. Trisomy 12 CLL cells with low expression of IRF4 upregulate NOTCH2, mediating the high expression of MCL-1. An increased copy number of the MCL-1 locus on chromosome 1q21 might increase MCL-1 expression. SMARCA4 gene deletion, mutations in the SWI-SNF complex and the subsequently reduced chromatin accessibility of the transcriptional repressor ATF3 induce increased expression of BCL-XL. The release of IL-6 from mesenchymal cells directly upregulates the MCL-1 transcript via STAT-3. IL-6 promotes BIM phosphorylation, which dissociates BIM from BCL-2 and binds to MCL-1. In addition, reduced miR-193b-3p expression in bone marrow stromal cells mediates MCL-1 upregulation, while upregulation of miR-21-5p reduces BCL-2 levels (Created with BioRender.com).