Deciphering the Molecular Mechanisms of Apoptosis: Recent Advances in Controlled Cell Death Pathways

Apoptosis is a genetically encoded and meticulously controlled cellular self-destruction program, fundamental to embryogenesis, tissue equilibrium, immune function, and the removal of compromised or dangerous cells. Unlike necrosis, apoptosis unfolds via a coordinated molecular cascade that maintains the plasma membrane's integrity and avoids inciting inflammation. Mechanistically, apoptosis is driven by a family of cysteine proteases called caspases. Their activation occurs primarily through two routes: the extrinsic pathway, triggered by death receptor activation, and the intrinsic pathway, regulated by mitochondrial events. A key regulatory checkpoint of the intrinsic pathway is mitochondrial outer membrane permeabilization (MOMP), a process controlled by interactions among members of the B-cell lymphoma-۲ (Bcl-۲) protein family. In parallel, the inhibitor of apoptosis (IAP) proteins provides an additional regulatory layer by restraining caspase activity downstream of mitochondrial signaling. Dysregulation of these apoptotic networks is a defining feature of numerous human diseases, including cancer, autoimmune disorders, neurodegeneration, and ischemic injury. Advances in understanding apoptotic control mechanisms have facilitated the development of targeted therapeutic strategies, such as BH۳-mimetics and SMAC mimetics, aimed at modulating cell death susceptibility in disease-specific contexts. This review synthesizes current insights into the molecular architecture of apoptosis, highlighting key regulatory checkpoints, pathway integration, and emerging therapeutic opportunities.

کلیدواژه ها:

Mitochondrial outer membrane permeabilization (MOMP) ، Death receptors ، BH۳-mimetics ، SMAC mimetics ، Efferocytosis