BH3-only pro-apoptotic Bcl-2 family proteins (BH3-only proteins)

BH3-only pro-apoptotic Bcl-2 family proteins are a subgroup of the Bcl-2 family that serve as critical initiators of the intrinsic apoptotic pathway in response to cellular stress (Shamas-Din et al., 2011). This group includes proteins such as BIM, PUMA, BID, and NOXA, which possess only the third Bcl-2 homology (BH3) domain required for their pro-apoptotic activity (Youle & Strasser, 2008). They function by sensing internal damage—such as DNA damage or oncogenic signaling—and subsequently neutralizing anti-apoptotic proteins like BCL-2, BCL-XL, and MCL-1, or directly activating the executioner proteins BAX and BAK (Montero & Letai, 2018). In many cancers, the evasion of apoptosis is achieved through the overexpression of anti-apoptotic proteins that sequester BH3-only proteins, preventing them from triggering cell death (Delbridge et al., 2016). Therapeutic intervention focuses on "BH3 mimetics," small molecules that mimic the action of BH3-only proteins to occupy the binding grooves of anti-apoptotic targets, thereby releasing the "pro-death" signal (Cang et al., 2015). Venetoclax is the first FDA-approved BH3 mimetic, demonstrating significant clinical efficacy in hematologic malignancies by specifically inhibiting BCL-2 (FDA, 2016).

Other names

BH3-only proteinsBH3-only Bcl-2 family membersPro-apoptotic BH3-only proteins

BH3 mimetics function by binding to the hydrophobic groove of anti-apoptotic Bcl-2 family members (such as BCL-2, BCL-XL, or MCL-1), thereby displacing sequestered pro-apoptotic BH3-only proteins or preventing the sequestration of BAX and BAK, which leads to mitochondrial outer membrane permeabilization (MOMP) and subsequent apoptosis (Cang et al., 2015).