The dual role of VDAC in cancer: Molecular mechanisms and advances in targeted therapy.

The voltage-dependent anion channel (VDAC) family proteins can be subdivided into three isoforms: VDAC1, VDAC2, and VDAC3. As core channels of the mitochondrial outer membrane, these proteins exhibit paradoxical regulatory roles in cancer development. This review systematically summarizes their structural and functional characteristics, as well as the contradictory mechanisms in tumorigenesis and progression.On the one hand, VDAC1 mediates channel closure by binding to the C-terminal tails (CTTs) of tubulins, enhances glycolysis through interaction with hexokinase to promote aerobic glycolysis (Warburg effect), stabilizes mitochondrial membrane potential, inhibits reactive oxygen species (ROS) production, and collaborates with the BNIP3/PINK1-Parkin pathway to regulate mitophagy, thereby facilitating tumor immune escape and metabolic adaptation. On the other hand, tubulin antagonists like erastin induce VDAC1/2 opening to reverse the Warburg effect, killing cancer cells via ferroptosis, and its oligomerization state can reverse apoptotic resistance. Advances in targeted therapy show that compounds based on VDAC gating regulation (such as avicin/acrolein for channel closure and erastin/betulinic acid for channel opening) exhibit significant antitumor effects in models of lung cancer, breast cancer, etc. Moreover, the interaction between TSPO and VDAC, as well as oligomerization regulation mediated by GPCPD1, have emerged as novel strategies.This review highlights the functional heterogeneity of VDAC isoforms and the challenges posed by ROS concentration thresholds for precision therapy, providing a theoretical basis for developing cancer treatment strategies targeting mitochondrial channels.