The CNC-family transcription factor NRF3: A crucial therapeutic target for cancer treatment

Abstract

The CNC-bZIP family member NRF3 (NFE2L3) has received limited attention since its discovery. However, recent research has gradually revealed its biological functions, such as involvement in the regulation of cell differentiation, lipid metabolism, and malignant cell proliferation. Under physiological conditions, NRF3 is anchored to the endoplasmic reticulum within the cytoplasm and is biologically inactive. Upon cellular exposure to microenvironmental stresses such as oxidative stress, NRF3 translocates to the nucleus, binds to DNA, and acts as a transcription factor by inducing or repressing the expression of various genes. In terms of tumor regulation, NRF3 exhibits a dual role. It can function as a tumor suppressor to prevent the malignant progression of tumor tissues, protecting the organism from harm. Conversely, current research indicates that NRF3 plays a tumor-promoting role in most tumor tissues. NRF3 enhances the proliferation, migration and invasion of tumor cells by regulating cell cycle-related proteins and enhancing proteasome assembly to degrade tumor suppressors. Studies correlating NRF3 expression with clinical tumor features have found that elevated NRF3 expression is often associated with poor prognoses in various cancers, with patients exhibiting higher NRF3 expression typically having lower survival rates. Several studies suggest that NRF3 could serve as a clinical diagnostic and prognostic marker for tumors. Finally, from the clinical perspective, exploring the feasibility of inhibiting NRF3 activity in tumor treatment provides new insights for the development of NRF3-targeted oncological therapies.