B-cell lymphoma 2 family-regulated apoptotic pathway (BCL2 pathway)

The B-cell lymphoma 2 (BCL2) family-regulated apoptotic pathway is a fundamental cellular mechanism that controls the intrinsic or mitochondrial pathway of programmed cell death [1]. This pathway is governed by the interaction between three groups of proteins: anti-apoptotic members (e.g., BCL2, BCL-XL, MCL1), pro-apoptotic effectors (BAX, BAK), and pro-apoptotic BH3-only initiators (e.g., BIM, PUMA, BAD) [2]. In many malignancies, cancer cells overexpress anti-apoptotic proteins to sequester pro-apoptotic molecules, thereby evading apoptosis and promoting survival despite oncogenic stress or chemotherapy [3]. Therapeutic strategies targeting this pathway primarily utilize BH3 mimetics, which are small molecules that occupy the binding grooves of anti-apoptotic proteins, releasing pro-apoptotic effectors to induce mitochondrial outer membrane permeabilization (MOMP) [4]. Venetoclax is the first-in-class BCL2-selective inhibitor approved for treating chronic lymphocytic leukemia and acute myeloid leukemia [5]. While highly effective, targeting this pathway requires careful management of safety concerns such as tumor lysis syndrome and lineage-specific toxicities like thrombocytopenia [6].

Other names

Intrinsic apoptotic pathwayMitochondrial apoptotic pathwayBCL2-mediated apoptosisMitochondrial outer membrane permeabilization (MOMP) pathway

BH3 mimetics bind to the hydrophobic groove of anti-apoptotic BCL2 family proteins, displacing pro-apoptotic proteins like BIM, BAX, and BAK to trigger mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation.