Caveolin-1–Nuclear factor erythroid 2-related factor 2 signaling axis (CAV1–Nrf2 axis)

The Caveolin-1–Nuclear factor erythroid 2-related factor 2 (CAV1–Nrf2) signaling axis is a critical regulatory mechanism that links plasma membrane structural integrity with the cellular antioxidant response [PubMed: 22416018]. Caveolin-1, a primary scaffolding protein of caveolae, directly interacts with the transcription factor Nrf2, typically sequestering it in the cytoplasm and inhibiting its ability to drive the expression of cytoprotective genes [UniProt: P14416]. This interaction is mediated by the caveolin-scaffolding domain (CSD) of CAV1 and the Nrf2-ECH homology (Neh) domains of Nrf2 [PubMed: 28636914]. Dysregulation of this axis is implicated in various pathologies; for instance, loss of CAV1 can lead to constitutive Nrf2 activation, which may promote chemoresistance in cancer cells, while CAV1 overexpression can suppress Nrf2, exacerbating oxidative damage in conditions like pulmonary fibrosis and cardiovascular disease [NCBI: PMC4688118]. Therapeutic interventions targeting this axis generally utilize Nrf2 activators, such as Sulforaphane or Bardoxolone methyl, to disrupt inhibitory complexes and restore redox homeostasis [PubMed: 23972477]. Understanding the balance within this axis is crucial for developing targeted therapies that address oxidative damage without inadvertently promoting tumor cell survival.

Other names

CAV1-Nrf2 pathwayCaveolin-1/NFE2L2 signaling axisCAV1-NFE2L2 complexCaveolin-1-Nrf2 interaction

The mechanism of action involves the pharmacological disruption of the inhibitory interaction between Caveolin-1 and Nrf2, or the modification of Keap1, leading to the stabilization and nuclear translocation of Nrf2 [PubMed: 22416018]. Once in the nucleus, Nrf2 binds to the Antioxidant Response Element (ARE) in the promoter regions of target genes, inducing the transcription of antioxidant and phase II detoxification enzymes such as Heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) [NCBI: PMC4688118].