VDAC2: an emerging pivotal and multifaceted regulator in tumor biology.

Voltage-dependent anion channel 2 (VDAC2) is a pivotal β-barrel protein located in the mitochondrial outer membrane (MOM), playing a central role in metabolite transport, ion homeostasis, and the determination of cell fate. Compared to other isoforms in the same family, VDAC2 possesses unique structural features-including an N-terminal extension, an enrichment of cysteine residues, and a distinct β-barrel conformation-which underlie its non-redundant functional roles. Notably, VDAC2 acts as a "dual regulatory hub" in apoptosis: it suppresses apoptosis by directly binding and inhibiting BAK, while also being essential for BAX-mediated apoptosis, demonstrating marked context-dependency. Furthermore, VDAC2 is deeply involved in tumor progression through its regulation of metabolic reprogramming, reactive oxygen species (ROS) homeostasis, ferroptosis, and mitochondrial quality control. Dysregulation of VDAC2 expression is closely associated with prognosis in multiple cancers, highlighting its promise as a diagnostic and prognostic biomarker, as well as a therapeutic target. This review systematically consolidates current knowledge on VDAC2 in oncology, identifies limitations and challenges in existing research, and aims to offer strategic insights to guide future investigations.