Multifaceted Roles of Bcl-2 Family Proteins: Regulatory Roles in Apoptosis, Physiological Functions, and Therapeutic Potential

Abstract

Bcl-2 family proteins (BFPs) are essential regulators of regulated cell death (RCD), and their dysregulation is implicated in a wide range of disorders, including cancer, neurodegenerative diseases, and autoimmune conditions. Recent studies have shown that BFPs also play critical roles in autophagy, calcium homeostasis, neuronal function, and mitochondrial dynamics, underscoring their multifaceted contributions to cellular health. In this review, we summarize the current knowledge concerning the physiological roles and structural diversity of BFPs, with a particular focus on key multidomain proteins such as Bak, Bax, and Bok. Our findings highlight persistent challenges and knowledge gaps, especially concerning the interactions between BFPs and diverse cellular pathways. In conclusion, BFPs act as fundamental regulators of cell survival and apoptosis. While significant progress has been made in elucidating their molecular mechanisms, important questions remain—particularly regarding the precise structural dynamics of pore formation, the influence of the mitochondrial lipid composition, and the balance between pro- and anti-apoptotic members. Finally, the therapeutic potential of BFP-targeted drugs, including BH3 mimetics, offers promising avenues for treating cancer and other diseases characterized by aberrant regulation of apoptosis.

Keywords

Bcl-2 / Bax / Bak / Apoptosis / Mitochondrial dynamics / BH3 mimetics / Therapeutic target / Cell death regulation

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