TRIM25 promotes glioblastoma progression by stabilizing HIF-1α expression in normoxia through K11/K29 polyubiquitination

  • Cell Death Dis. 2026 Apr 22;17(1):530. doi: 10.1038/s41419-026-08757-3.
Hui Huang  #  1 ,  Kaixiang Ni  #  2  3 ,  Chenhua Li  #  1 ,  Maorong Cai  #  1 ,  Yuankun Liu  1 ,  Jiahao Zhang  1 ,  Yifan Shen  1 ,  Yuning Chen  1 ,  Jun Sun  4 ,  Junfei Shao  5 ,  Yi Liu  6  7 ,  Wei Ji  8 ,  Jiantong Jiao  9
Affiliations
  • 1. Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.
  • 2. Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada.
  • 3. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
  • 4. Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 5. Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 6. Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada. [email protected].
  • 7. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. [email protected].
  • 8. Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 9. Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 42020378 DOI: 10.1038/s41419-026-08757-3
Abstract

Glioblastoma (GBM) frequently activates hypoxia signaling even under normoxic conditions, yet the mechanism sustaining hypoxia-inducible factor-1α (HIF-1α) stability remains unclear. Here, we identify the E3 ubiquitin Ligase TRIM25 as a key driver of this phenomenon. TRIM25, aberrantly upregulated in GBM, directly binds HIF-1α and catalyzes K11/K29-linked polyubiquitination at lysine 532 of hydroxylated HIF-1α, preventing its canonical proteasomal degradation. This non-canonical ubiquitin modification stabilizes HIF-1α despite normal oxygen availability and sustains a pseudohypoxic transcriptional program in GBM cells. Functional studies in GBM cell lines, patient-derived cultures, and tumor models demonstrate that TRIM25-mediated HIF-1α stabilization promotes tumor proliferation, invasion, and angiogenic potential. Importantly, small-molecule screening identified T7117 as an inhibitor that disrupts the TRIM25-HIF-1α interaction, suppresses tumor growth, and enhances temozolomide efficacy. Together, our findings uncover a previously unrecognized ubiquitin mechanism that stabilizes hydroxylated HIF-1α under normoxia, revealing the TRIM25-HIF-1α axis as a driver of GBM pseudohypoxia and a potential therapeutic target.

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