Mcl-1

Mcl-1 (myeloid cell leukemia-1) is a critical anti-apoptotic member of the BCL-2 protein family that preserves mitochondrial integrity by restraining the pro-apoptotic effectors BAK and BAX and preventing mitochondrial outer membrane permeabilization (MOMP)^[1][2]. Mechanistically, Mcl-1 contains a hydrophobic BH3-binding groove that sequesters pro-apoptotic proteins and suppresses stress-induced apoptosis, thereby maintaining cell survival under physiological and pathological conditions^[1][3]. Within the intrinsic apoptotic pathway, BH3-only proteins including NOXA, BIM, PUMA, and BID antagonize anti-apoptotic BCL-2 family members, and NOXA displays notable selectivity toward Mcl-1, promoting apoptotic signaling through Mcl-1 neutralization and degradation^[4][5][6]. In cancer models, Mcl-1 overexpression contributes to tumor progression, chemoresistance, and disease relapse, highlighting its role as a major survival factor in malignant cells^[7][8]. Compared with related anti-apoptotic isoforms such as BCL-2 and BCL-xL, Mcl-1 exhibits distinct binding preferences and plays a particularly important role in restraining BAK-dependent apoptosis, indicating non-redundant functions within the BCL-2 family network^[9][10]. For experimental applications, selective Mcl-1 inhibitors and BH3 mimetics, including MCL-1 SAHB and S63845, disrupt Mcl-1-BAK interactions and induce apoptosis in MCL-1-dependent cancer cells, providing valuable tools for mechanistic studies and therapeutic target validation^[11][12].