This review article provides a comprehensive overview of the NF-κB signaling pathway, its biological functions, and its role in various diseases. NF-κB signaling, initially identified for its role in inflammatory responses, has been expanded to include a wide range of signaling mechanisms and biological processes. The article details the composition, activation, and regulatory mechanisms of NF-κB signaling, including its interaction with other key pathways such as PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. It also explores the physiological and pathological states of NF-κB signaling, highlighting its involvement in inflammation, immune regulation, and tumor microenvironment. The article further discusses therapeutic approaches targeting NF-κB signaling, such as IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T therapy. Finally, the article provides an outlook for future research in the field of NF-κB signaling, emphasizing the need for a deeper understanding of its complex mechanisms to inform clinical practice and gene manipulation.This review article provides a comprehensive overview of the NF-κB signaling pathway, its biological functions, and its role in various diseases. NF-κB signaling, initially identified for its role in inflammatory responses, has been expanded to include a wide range of signaling mechanisms and biological processes. The article details the composition, activation, and regulatory mechanisms of NF-κB signaling, including its interaction with other key pathways such as PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. It also explores the physiological and pathological states of NF-κB signaling, highlighting its involvement in inflammation, immune regulation, and tumor microenvironment. The article further discusses therapeutic approaches targeting NF-κB signaling, such as IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T therapy. Finally, the article provides an outlook for future research in the field of NF-κB signaling, emphasizing the need for a deeper understanding of its complex mechanisms to inform clinical practice and gene manipulation.