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Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, represents a substantial global health challenge with limited treatment options. The voltage‑dependent anion channel (VDAC), a critical mitochondrial outer membrane protein, has emerged as a pivotal regulator in HCC pathogenesis. Dysregulation of VDAC expression and function disrupts mitochondrial metabolism, confers resistance to apoptosis and promotes tumor proliferation. Mechanistically, VDAC facilitates HCC progression through metabolic reprogramming, evasion of programmed cell death and crosstalk with multiple oncogenic signaling pathways. Current VDAC‑targeted therapeutic approaches, including small‑molecule inhibitors and metabolic modulators, have demonstrated promising preclinical efficacy in inducing apoptosis and suppressing tumor growth. Notably, these agents may overcome therapeutic resistance and exhibit synergistic effects with conventional therapies. However, several challenges persist, particularly in elucidating isoform‑specific functions, optimizing pharmacokinetic profiles and identifying predictive biomarkers for patient stratification. The present comprehensive review critically evaluates the mechanistic involvement of VDAC in HCC progression, assesses emerging targeting strategies and proposes future research directions to establish VDAC as a viable precision medicine target for HCC management.