The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein.

Many cancers exhibit resistance to chemotherapy, resulting in a poor prognosis. The transcription factor NRF2, activated in response to cellular antioxidants, plays a crucial role in cell survival, proliferation, and resistance to chemotherapy. This factor may serve as a promising target for therapeutic interventions in esophageal carcinoma. Recent research suggests that NRF2 activity is modulated by ubiquitination mediated by the KEAP1-CUL3 E3 ligase complex, highlighting the importance of deubiquitination. However, the specific deubiquitinase responsible for regulating NRF2 in esophageal cancer remains unknown. In this study, a novel regulator of the NRF2 protein, Ubiquitin-Specific Protease 35 (USP35), has been identified. Mechanistically, USP35 modulates NRF2 stability through enzymatic deubiquitination. USP35 interacts with NRF2 and facilitates its deubiquitination. Knockdown of USP35 leads to a notable increase in NRF2 levels and enhances the sensitivity of cells to chemotherapy. These findings suggest that the USP35-NRF2 axis is a key player in the regulation of therapeutic strategies for esophageal cancer.