VDAC3 is a voltage-gated ion channel mediating anion and cation transport across the mitochondrial outer membrane 1. It forms a high-conducting channel with voltage-induced closure showing mild anion preference 1. VDAC3 is central to ferroptosis regulation in cancer. Erastin, a ferroptosis activator, binds directly to VDAC3 and VDAC2, triggering iron-dependent oxidative cell death in RAS-mutant tumors 2. However, cells develop resistance through Nedd4-mediated ubiquitination of VDAC2/3, leading to channel degradation 3. BRCA1 transcriptionally activates VDAC3 and GPX4; BRCA1 deficiency blocks VDAC3 expression, conferring erastin resistance but creating vulnerability to GPX4 inhibition 4. Beyond ferroptosis, VDAC3 participates in mitochondrial quality control—TMX2 recruits parkin to VDAC2/3-containing defective mitochondria to promote cytoprotective mitophagy 5. A circular RNA derived from VDAC3 (crVDAC3) accumulates HSPB1 protein, suppressing ferroptosis and mediating trastuzumab deruxtecan resistance in HER2-low breast cancer 6. Additionally, VDAC3 functions in ER-mitochondria iron crosstalk, interacting with ZIP7 via ACSL4 to regulate mitochondrial iron homeostasis 7. These multifaceted roles position VDAC3 as a therapeutic target for overcoming cancer drug resistance.