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

Constitutive activation of the transcription factor NRF2 confers therapeutic resistance in glioblastoma (GBM), however, this hyperactivation frequently persists despite the presence of intact KEAP1, suggesting the existence of KEAP1-independent regulatory mechanisms. Here, we identify the E3 ubiquitin ligase SMURF2 as a key nuclear regulator that restricts NRF2 activity and attenuates tumor progression. We demonstrate that SMURF2 overexpression suppresses the NRF2-mediated adaptive response to oxidative and proteotoxic stress, thereby reducing protein aggregation and promoting apoptosis. Mechanistically, cellular stress triggers the nuclear translocation of SMURF2, where it interacts with and degrades nuclear NRF2 via K48-linked polyubiquitination, independently of the canonical KEAP1 pathway. Consequently, a mutation in the nuclear localization sequence (NLS) of SMURF2 prevents its nuclear localization and fails to degrade NRF2. Additionally, the expression of an ubiquitination-resistant NRF2 mutant (K555R) prevents NRF2 degradation and abolishes stress-induced apoptosis. Clinically, high SMURF2 expression correlates with improved survival in patients with GBM exhibiting constitutive NRF2 activation. These findings uncover a novel axis of NRF2 regulation and highlight SMURF2 as a potential therapeutic target for NRF2-driven malignancies.