Phosphoinositide 3-kinase–Akt–nuclear factor erythroid 2-related factor 2 pathway (PI3K–Akt–Nrf2 pathway)

The **phosphoinositide 3‑kinase–Akt–nuclear factor erythroid 2-related factor 2 (PI3K–Akt–Nrf2) pathway** is a critical intracellular signaling cascade that integrates signals from growth factors and oxidative stress to regulate cell survival, metabolism, proliferation, and antioxidant defenses. Activation begins with phosphoinositide 3‑kinase (PI3K), which phosphorylates membrane lipids leading to activation of protein kinase B (Akt). Activated Akt promotes cellular survival pathways while also acting upstream to activate nuclear translocation of the transcription factor Nrf2. Once activated by phosphorylation via the PI3K/Akt axis—especially under conditions like oxidative stress—Nrf2 induces expression of a suite of antioxidant genes including heme oxygenase‑1 (HO‑1) and NAD(P)H quinone dehydrogenase (NQO1). This coordinated response helps detoxify reactive oxygen species (ROS), maintain redox homeostasis via glutathione synthesis pathways regulated by NADPH production from the pentose phosphate shunt—and supports anabolic processes important for both normal physiology and cancer progression. Dysregulation contributes to diseases such as cancer through enhanced ROS detoxification supporting tumor growth; it also plays roles in neurodegeneration and age-associated tissue dysfunction due to impaired antioxidative capacity with aging. Note on correctness: The submitted target name refers not to a single molecule but rather an entire **signaling cascade** composed primarily of three distinct proteins/complexes—PI3K enzyme(s), Akt kinase(s), and the transcription factor Nrf２—not a canonical drug target itself but rather a functional network often targeted at specific nodes for therapeutic intervention.

Other names

PI3K/Akt/Nrf2 signaling pathwayPhosphoinositide 3-kinase/Akt/nuclear factor erythroid-derived factor 2-related factor pathwayPI3K-Akt-Nrf2 axis

Drugs targeting this pathway may act by inhibiting or activating one or more components to modulate cell survival, antioxidant responses, or metabolic activity. For example, • Inhibition of PI3K/Akt can suppress tumor growth. • Activation of Nrf2 enhances antioxidant gene expression for cytoprotection against oxidative damage.