PMAIP1 (also called NOXA) is a BH3-only pro-apoptotic protein that drives programmed cell death through multiple interconnected pathways. It promotes activation of caspases, mitochondrial outer membrane permeabilization, and cytochrome c release, while also competing with BAK1 and BIM for binding to the anti-apoptotic protein MCL1, thereby displacing these regulators and promoting MCL1 proteasomal degradation. PMAIP1 plays a central role in p53-dependent apoptosis following DNA damage and responds to cellular stress including glucose starvation, hypoxia, and viral infection. In acute myeloid leukemia (AML), PMAIP1 is critical for therapeutic efficacy. The hypomethylating agent 5-azacitidine induces PMAIP1 expression through the integrated stress response pathway, priming AML cells for apoptosis by the BCL-2 inhibitor venetoclax 1. PMAIP1 is essential for venetoclax response—inactivation of PMAIP1 confers resistance to the drug 2. Similarly, parthenolide induces PMAIP1 upregulation alongside MCL1 downregulation to trigger apoptosis in non-small cell lung cancer, with PMAIP1 knockdown conferring protection from drug-induced death 3. Novel venetoclax-based conjugates that enhance NOXA production overcome Mcl-1 and Bcl-xL-mediated resistance in AML 4. Recent evidence suggests PMAIP1 may contribute to mitochondrial dysfunction in Alzheimer's disease 5, and genomic studies associate PMAIP1 with both lipid metabolism and coronary heart disease risk 6. USP28 inhibitors and LSD1 PROTACs activate NOXA-mediated apoptosis in lung and breast cancers 7, 8, establishing PMAIP1 as a convergence point for pro-apoptotic drug strategies.