Pro-apoptotic proteins

Pro-apoptotic proteins are a functional class of molecules that initiate or execute programmed cell death, a process essential for maintaining tissue homeostasis and removing damaged or potentially malignant cells (Montero & Letai, 2018). This group primarily includes the pro-apoptotic members of the Bcl-2 family, such as the effectors BAX and BAK, and the BH3-only proteins like BIM, PUMA, and NOXA, as well as the caspase family of proteases (Shalini et al., 2015). In healthy cells, these proteins are typically sequestered or neutralized by anti-apoptotic proteins like BCL-2, BCL-XL, or MCL-1. However, in response to cellular stress or DNA damage, pro-apoptotic proteins are activated, leading to mitochondrial outer membrane permeabilization (MOMP) and the subsequent release of cytochrome c, which triggers the executioner caspase cascade (You et al., 2022). In many cancers, the balance of these proteins is disrupted, favoring survival and resistance to therapy, which has led to the development of BH3 mimetics like venetoclax that restore apoptotic signaling (Czabotar et al., 2014). Beyond oncology, the dysregulation of pro-apoptotic proteins is a significant factor in neurodegenerative diseases and autoimmune conditions, where cell death is either excessive or insufficient, respectively (Singh et al., 2019).

Other names

Death-promoting proteinsPro-apoptotic Bcl-2 family membersBH3-only proteinsEffector pro-apoptotic proteinsApoptotic executioners

BH3 mimetics inhibit anti-apoptotic proteins to release pro-apoptotic effectors; direct activation of BAX/BAK; induction of the caspase cascade.