Li, K.Yap, Y.Q.Moujalled, D.M.Sumardy, F.Khakham, Y.Georgiou, A.Jahja, M.Lew, T.E.De Silva, M.Luo, M.X.Gong, J.N.Yuan, Z.Birkinshaw, R.W.Czabotar, P.E.Lowes, K.Huang, D.C.S.Kile, B.T.Wei, A.H.Dewson, G.van Delft, M.F.et al.2025-07-292025-07-292025Science Advances, 2025; 11(10):eadr8146-1-eadr8146-142375-25482375-2548https://hdl.handle.net/2440/146398Defective apoptosis mediated by B cell lymphoma 2 antagonist/killer (BAK) or B cell lymphoma 2-associated X protein (BAX) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with BAK and BAX through a common interface to inhibit BAK or to facilitate BAX apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and BAK or BAX revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, apoptosis promotion by WEHI-3773 dominates, because activated BAK activates BAX through a feed-forward mechanism. Loss of BAX drives resistance to the BCL-2 inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of BAX and BAK apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.enCopyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. Distributed under acreative commons Attribution NonCommercial License 4.0 (CC BY-NC).apoptosis; mitochondria; apoptotic activity; BAX; BAKCell Line, TumorMitochondriaAnimalsHumansApoptosisProtein BindingVoltage-Dependent Anion Channel 2bcl-2 Homologous Antagonist-Killer Proteinbcl-2-Associated X ProteinSmall Molecule LibrariesJournal article10.1126/sciadv.adr8146731693Kile, B.T. [0000-0002-8836-8947]