cAMP response element-binding protein 1-Nuclear factor erythroid 2-related factor 2 signaling pathway (CREB1-NRF2 signaling pathway) (CREB1-NRF2)

The cAMP response element-binding protein 1-Nuclear factor erythroid 2-related factor 2 (CREB1-NRF2) signaling pathway is a critical regulatory axis that integrates cAMP-mediated signaling with the cellular antioxidant response [1.2.1, 1.3.1]. CREB1 acts as an upstream transcription factor that, upon activation by kinases like PKA, promotes the expression and nuclear translocation of NRF2, the master regulator of redox homeostasis [1.2.2, 1.3.3]. Together, they co-regulate the transcription of a wide array of cytoprotective genes, including heme oxygenase-1 (HO-1) and enzymes involved in glutathione synthesis, thereby protecting cells from oxidative stress, inflammation, and apoptosis [1.2.1, 1.4.2]. This pathway is a significant therapeutic target in neurodegenerative diseases, cardiovascular conditions, and chronic inflammatory disorders due to its potent cytoprotective effects [1.1.1, 1.2.3]. However, its constitutive activation in various cancers can promote tumor cell survival and resistance to chemotherapy, a phenomenon known as 'NRF2 addiction' [1.1.2, 1.2.5]. Therapeutic strategies involve using CREB activators like forskolin to enhance antioxidant defenses or NRF2 inhibitors to sensitize cancer cells to treatment [1.2.2, 1.2.5].

Other names

CREB-NRF2 axisCREB1-NFE2L2 pathwaycAMP-NRF2 signalingCREB1-NRF2 crosstalk

Activation of CREB1 leads to increased NRF2 expression and activity, which induces the transcription of cytoprotective and antioxidant genes; inhibition of the pathway suppresses these protective mechanisms.