AMP-activated protein kinase–Nuclear factor erythroid 2-related factor 2 signaling pathway (AMPK–Nrf2 pathway) (AMPK–Nrf2 pathway)

The AMP-activated protein kinase–Nuclear factor erythroid 2-related factor 2 (AMPK–Nrf2) signaling pathway is a critical cellular axis that integrates metabolic status with the antioxidant response. AMPK acts as a master energy sensor, becoming activated during periods of metabolic stress or low ATP levels (Hardie et al., 2012, Chem Biol). Once activated, AMPK facilitates the nuclear translocation of Nrf2, a transcription factor that coordinates the expression of a battery of cytoprotective and antioxidant genes (Joo et al., 2016, Nature). This pathway is essential for maintaining redox homeostasis and has been implicated in the pathophysiology of various conditions, including type 2 diabetes, neurodegenerative diseases, and chronic inflammation (Loboda et al., 2016, Free Radic Biol Med). Therapeutic strategies often involve the use of AMPK activators like metformin or Nrf2 inducers like dimethyl fumarate to enhance cellular defenses (Zimmermann et al., 2015, Free Radic Biol Med). However, the pathway's role in cancer is dualistic; while it can prevent tumor initiation, Nrf2 activation in established tumors can promote cancer cell survival and resistance to therapy (Wang et al., 2008, Carcinogenesis). Thus, while the AMPK–Nrf2 axis is a promising therapeutic target, its modulation requires precise timing and context-specific application.

Other names

AMPK-Nrf2 axisAMPK-Nrf2-ARE signaling pathwayAMPK-Nrf2 antioxidant response

AMPK activation promotes the phosphorylation of Nrf2 at Ser558, facilitating its nuclear translocation and subsequent binding to Antioxidant Response Elements (ARE) to induce the expression of cytoprotective genes (Joo et al., 2016, Nature; Itoh et al., 1997, Biochem Biophys Res Commun).