HK2/VDAC1 Axis Regulates Malignant Progression of Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with limited effective therapies. Although hexokinase 2 (HK2) is upregulated in multiple cancers, its role in ESCC progression and underlying mechanisms, particularly its interaction with the mitochondrial damage pathway, remains incompletely understood.

Bioinformatic analyses and clinical specimens were used to evaluate HK2 expression in ESCC and its association with prognosis. Functional assays, including CCK-8, wound healing, Transwell, flow cytometry, ROS detection, JC-1 staining, and mitochondrial protein analyses, were performed in ESCC cells with HK2 overexpression or knockdown. Co-immunoprecipitation (CO-IP) was conducted to validate the physical interaction between HK2 and VDAC1. A subcutaneous xenograft model was used to assess the pro-tumorigenic role of HK2 in vivo.

HK2 was markedly overexpressed in ESCC and was associated with poor prognosis. Mechanistically, HK2 interacted with VDAC1 on the outer mitochondrial membrane, suppressed mitochondrial depolarization and ROS accumulation, protected mitochondrial function, and thereby promoted ESCC cell proliferation, migration, and invasion. Conversely, HK2 knockdown disrupted HK2-VDAC1-associated mitochondrial regulation, induced mitochondrial dysfunction and apoptosis, and attenuated malignant phenotypes. In vivo, HK2 overexpression promoted tumor growth, whereas HK2 knockdown significantly suppressed tumor progression.

These findings suggest that HK2 promotes ESCC progression at least partly by interacting with VDAC1, protecting mitochondrial function and reducing cell apoptosis. The HK2-VDAC1 axis may represent a potential therapeutic vulnerability in ESCC.