Glycogen synthase kinase-3 beta and nuclear factor erythroid 2-related factor 2 signaling axis (GSK-3β/Nrf2 pathway)

The GSK-3β/Nrf2 signaling pathway refers to the regulatory relationship in which Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, negatively regulates nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor pivotal in cellular antioxidant defenses. GSK-3β can directly phosphorylate Nrf2, promoting its nuclear export and proteasomal degradation independently of the classical Keap1 pathway. Furthermore, GSK-3β influences Nrf2 indirectly via activation of Fyn kinase, which in turn exports and suppresses Nrf2 in the nucleus. Disruption or modulation of this pathway has been implicated in a range of diseases—especially those associated with oxidative stress, such as neurodegenerative disorders, cancer, diabetes (delayed wound healing), and inflammatory conditions. Pharmacological inhibition of GSK-3β stabilizes Nrf2, increases antioxidant gene expression, and is under investigation as a potential therapeutic strategy. The axis is a subject of interest for developing new multi-targeted therapies, particularly for neurodegeneration and chronic inflammation.

Other names

GSK-3β–Nrf2 axisGSK-3β–Nrf2 pathwayGSK-3β/Fyn/Nrf2 signaling

Inhibition of GSK-3β leads to stabilization and nuclear accumulation of Nrf2, promoting antioxidant gene expression; Direct Nrf2 activation (independent of GSK-3β); Inhibition of Nrf2 degradation (via GSK-3β inhibition); Modulation of Fyn kinase nuclear translocation (via GSK-3β activity)