Toll-like receptor 4 (TLR4) signaling pathway (TLR4/NF-κB/MAPK/Nrf2)

The TLR4–NF-κB/MAPK and Nrf2-related inflammatory/oxidative stress pathways represent a complex signaling network central to the regulation of innate immunity and cellular redox balance. Toll-like receptor 4 (TLR4) acts as a primary sensor for endotoxins, triggering the activation of Nuclear Factor-kappa B (NF-κB) and Mitogen-Activated Protein Kinases (MAPK) to initiate pro-inflammatory responses (UniProt: O00206). Simultaneously, the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is often activated as a protective response to counteract oxidative stress and limit excessive inflammation (PubMed: 29034071). Dysregulation of this axis, characterized by overactive TLR4 signaling and impaired Nrf2 activity, is a hallmark of chronic inflammatory diseases, sepsis, and neurodegeneration (PubMed: 30694468). Therapeutic strategies targeting this network include TLR4 antagonists like Resatorvid and Nrf2 activators, which aim to suppress cytokine storms and enhance antioxidant defenses (PubMed: 24011561).

Other names

TLR4-NF-kappaB-MAPK-Nrf2 axisTLR4/Nrf2 signaling axisInflammatory and oxidative stress signaling networkTLR4-mediated inflammatory pathwayNrf2-mediated antioxidant pathway

Inhibition of TLR4-mediated dimerization and downstream NF-κB/MAPK activation, coupled with the stabilization and nuclear translocation of Nrf2 to induce antioxidant response element (ARE)-driven gene expression.