Nuclear factor kappa B, Mitogen-activated protein kinase, and Signal transducer and activator of transcription 3 signaling pathways (NF-κB/MAPK/STAT3)

The NF-κB, MAPK, and STAT3 pathways represent three of the most critical signaling axes involved in the regulation of the inflammatory response and cellular homeostasis [1][2]. NF-κB is a primary transcription factor governing the expression of pro-inflammatory cytokines and cell survival genes, while the MAPK cascade (including ERK, JNK, and p38) translates extracellular stimuli into cellular responses like proliferation and stress adaptation [3][4]. STAT3, often activated by Janus kinases (JAKs) in response to cytokines like IL-6, serves as a key mediator of inflammation-associated gene expression and is frequently dysregulated in both autoimmune disorders and various cancers [5][6]. Together, these pathways form a complex, interconnected network where crosstalk ensures a coordinated response to pathogens and tissue injury [7]. Dysregulation of this network leads to chronic inflammatory states, promoting tumor progression, metastasis, and resistance to apoptosis [6][7]. Consequently, components of these pathways are major focal points for therapeutic intervention, with drugs ranging from monoclonal antibodies against upstream cytokines to small-molecule inhibitors of specific kinases within the cascades [2][5]. Citations: [1] Oeckinghaus A, Ghosh S. Cold Spring Harb Perspect Biol. 2009; [2] Taniguchi K, Karin M. Nat Rev Immunol. 2018; [3] Zhang W, Liu HT. Cell Res. 2002; [4] Kyriakis JM, Avruch J. Physiol Rev. 2012; [5] Yu H, et al. Nat Rev Cancer. 2014; [6] Grivennikov SI, Karin M. Cytokine Growth Factor Rev. 2010; [7] Fan Y, et al. Front Immunol. 2023.

Other names

NF-kappaB/MAPK/STAT3 axisPro-inflammatory signaling networkInflammatory signaling cascades

Drugs targeting these pathways typically act by inhibiting upstream receptors (e.g., TNF receptors), blocking intermediate kinases (e.g., JAK, MEK, IKK), or preventing the nuclear translocation and DNA binding of transcription factors to suppress the expression of pro-inflammatory and survival genes.