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SMURF2 attenuates NRF2-driven tumor progression by acting as a nuclear brake on NRF2 during cellular stress

Wanting Xu1, Lei Dong1, Jiaqian Li1

  • 1Advanced Technology Research Institute, State Key Laboratory of Hearing and Balance Science and Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), Aerospace Center Hospital, Tangshan Research Institute, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.

Redox Biology
|April 2, 2026
PubMed

Insights

SMURF2, a novel E3 ubiquitin ligase, restricts NRF2 activity in glioblastoma (GBM) through a KEAP1-independent pathway. High SMURF2 expression correlates with better patient survival, identifying it as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Constitutive NRF2 activation drives therapeutic resistance in glioblastoma (GBM).
  • KEAP1-independent mechanisms contribute to persistent NRF2 hyperactivation in GBM.
  • Novel regulators of NRF2 are crucial for understanding and overcoming GBM resistance.

Purpose of the Study:

  • To identify novel regulators of NRF2 activity in glioblastoma.
  • To elucidate the mechanism of KEAP1-independent NRF2 regulation.
  • To evaluate SMURF2 as a potential therapeutic target in GBM.

Main Methods:

  • Investigated the role of E3 ubiquitin ligase SMURF2 in NRF2 regulation.
  • Utilized cell-based assays to study NRF2 degradation and nuclear translocation.
  • Employed genetic mutations (SMURF2 NLS mutant, NRF2 K555R mutant) to dissect the pathway.
  • Correlated SMURF2 expression with patient survival data in GBM.

Main Results:

  • SMURF2 acts as a nuclear regulator that suppresses NRF2 activity and tumor progression.
  • SMURF2 overexpression reduces NRF2-mediated stress response, promoting apoptosis.
  • Cellular stress induces SMURF2 nuclear translocation, leading to KEAP1-independent NRF2 degradation via K48-linked polyubiquitination.
  • SMURF2 mutations impair NRF2 degradation and stress-induced apoptosis.
  • High SMURF2 expression correlates with improved survival in GBM patients with activated NRF2.

Conclusions:

  • SMURF2 is a novel E3 ligase that degrades nuclear NRF2 independently of KEAP1.
  • The SMURF2-NRF2 axis represents a new regulatory pathway in glioblastoma.
  • SMURF2 is a promising therapeutic target for NRF2-driven glioblastomas.
Keywords:
GlioblastomaNRF2Nucleus ubiquitinationProtein aggregatesSMURF2UPS

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