Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.

The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.