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

Sep 23, 2026

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Esophageal squamous cell carcinoma (ESCC) remains lethal with limited effective therapies. Hexokinase 2 (HK2) is upregulated across multiple cancers, yet its function in ESCC progression and its mechanism involving the mitochondrial damage pathway remain unclear. Bioinformatic and clinical specimen analyses evaluated HK2 expression and prognosis, while CCK-8, migration/invasion assays, flow cytometry, ROS and JC-1 measurements, and mitochondrial protein analyses assessed HK2 overexpression or knockdown. Co-immunoprecipitation confirmed HK2–VDAC1 interaction and xenograft studies tested in vivo effects. HK2 overexpression promoted malignant phenotypes and tumor growth, whereas HK2 knockdown induced mitochondrial dysfunction and apoptosis, indicating the HK2–VDAC1 axis as a therapeutic vulnerability.

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Abstract

Introduction

Cancer Medicine | RESEARCH ARTICLE OPEN ACCESS
HK2/VDAC1 Axis Regulates Malignant Progression of Esophageal Squamous Cell Carcinoma
Chenlu Dai1 | Jingyu Liu1 | Yaling Guan1 | Sensen Zhu1 | Mengjie Zhuang1 | Li Liu2 | Min Ji2 | Xuanming Liu1 | Ming Cheng1 | Linlin Zhang1 | Yan Ma3 | Liping Su2 | Hongwei Pu4,5,6
1School of Basic Medicine, Xinjiang Medical University, Urumqi, China | 2Department of Pathology, First Affliated Hospital, Xinjiang Medical University, Urumqi, China | 3Orthopaedics and Traumatology, Urumqi Chinese Medicine Hospital, Urumqi, China | 4State Key Laboratory of Pathogenesis, Prevention and Treatemt of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China | 5Department of Discipline Construction, First Affliated Hospital, Xinjiang Medical University, Urumqi, China | 6Key Laboratory of Forensic Medicine, Xinjiang Medical University, Urumqi, China
Correspondence: Hongwei Pu ([576250630@qq.com](576250630@qq.com)) | Yan Ma ([522744476@qq.com](522744476@qq.com)) | Liping Su ([1404720073@qq.com](1404720073@qq.com))
Received: 31 December 2025 | Revised: 24 June 2026 | Accepted: 2 July 2026
Keywords: apoptosis | esophageal squamous cell carcinoma | HK2 | tumor progression | VDAC1 | | | --- | --- | | ABSTRACT
Background: 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.
Methods: 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 andVDAC1. A subcutaneous xenograft model was used to assess the pro-tumorigenic role of HK2 in vivo.
Results: 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.
Conclusion: 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. | | | 1 | Introduction | cancer-related mortality globally [1] . China bears a particu- | | Esophageal cancer is one of the most common malignancies worldwide, ranking seventh in incidence and sixth in | larly heavy disease burden, accounting for nearly half of all newly diagnosed cases in 2019 [2] . Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of | | Chenlu Dai, Jingyu Liu, and Yaling Guan contributed equally to this article.
[Correction added on 10 August 2026, after first online publication: The authors Yan Ma and Liping Su have been added as co-corresponding authors.] | | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2026 The Author(s). Cancer Medicine published by J

FAQs

What is the main purpose of the study on HK2/VDAC1 in ESCC?

To determine how HK2 contributes to malignant progression of esophageal squamous cell carcinoma and to clarify its mechanism, especially its involvement in mitochondrial damage pathways via VDAC1 interaction.

How do the authors assess HK2’s effect on ESCC cells and mitochondria?

They use functional assays (CCK-8, wound healing, Transwell, flow cytometry), measure ROS levels and mitochondrial membrane potential with JC-1, analyze mitochondrial proteins, and compare HK2 overexpression versus knockdown.

What evidence supports that HK2 regulates ESCC progression through VDAC1?

Co-immunoprecipitation demonstrates physical interaction between HK2 and VDAC1, and mechanistic results show HK2 alters mitochondrial depolarization, ROS accumulation, mitochondrial function, and downstream proliferation/migration/invasion; xenografts further confirm tumor growth changes.

Sep 23, 2026

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