2. Academic Validation
  3. USP30-mediated Deubiquitination of Hexokinase 2 controls the metabolic fate of glucose and tumor progression

USP30-mediated Deubiquitination of Hexokinase 2 controls the metabolic fate of glucose and tumor progression

  • Cell Death Dis. 2026 Feb 14;17(1):225. doi: 10.1038/s41419-026-08459-w.
Zhang Haowei # 1 2,  Xiaolin Li # 2,  Weijie Liao # 3,  Xuan Qin 4,  Yapei Jiang 2,  Haitao Yang 2,  Hongli Zeng 2,  Yuetong Li 2,  Weidong Xie 2,  Yaou Zhang 2,  Naihan Xu 5 6
Affiliations

Affiliations

  • 1 School of Food and Drug, Shenzhen Polytechnic University, Shenzhen, China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.
  • 3 Department of Hematology and Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China.
  • 4 Fuwai Shenzhen Hospital, Chinese Academy of Medical Sciences, Shenzhen, China.
  • 5 School of Food and Drug, Shenzhen Polytechnic University, Shenzhen, China. [email protected].
  • 6 State Key Laboratory of Chemical Oncogenomics, Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 41688443 DOI: 10.1038/s41419-026-08459-w
Abstract

The mitochondria-localized Deubiquitinase USP30 regulates Mitophagy and mitochondrial homeostasis, playing a significant role in the progression of neurodegenerative diseases. However, its role in Cancer remains poorly understood. Through metabolism-related gene set enrichment analysis, we identified USP30 as a key modulator of glucose metabolism in Cancer cells. Utilizing quantitative proteomic and ubiquitinomic approaches coupled with co-immunoprecipitation assays, we elucidated that USP30 regulates glycolysis by interacting with Hexokinase HK1 and HK2, a process dependent on its enzymatic activity. USP30 modulates the ubiquitination profile of HK1 and HK2 by preferentially removing atypical ubiquitin chains, thereby enhancing their stability, mitochondrial localization, VDAC1 binding and Hexokinase activity. Lysine 144 emerges as a critical regulatory site for USP30-mediated deubiquitination of HK2. Mutation of K144 enhances HK2 stability, increases its mitochondrial localization and binding to VDAC1, and significantly augments Hexokinase activity. Furthermore, the HK2 K144 mutation markedly enhances tumor cell glycolysis, fostering increased proliferation and migration both in vitro and in vivo. These findings underscore USP30 as a novel regulator of glycolysis in Cancer cells via modulation of HK2 ubiquitination dynamics, suggesting its potential as a therapeutic target in Cancer metabolism.

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