NF-κB is a key transcription factor involved in inflammation and innate immunity, and increasingly recognized as crucial in cancer initiation and progression. It interacts with various signaling molecules and pathways, including other transcription factors like STAT3, p53, and ERG, as well as kinases such as GSK3-β, p38, and PI3K. These interactions can either directly affect NF-κB subunits or influence its target genes. Other molecules, such as reactive oxygen species and miRNAs, also play roles in crosstalk with NF-κB. The complexity of NF-κB signaling is further increased by differential DNA-binding preferences of different dimers and post-translational modifications that affect its activity and interactions with other pathways. NF-κB signaling is activated through various pathways, including canonical, non-canonical, and atypical routes, each with distinct mechanisms and roles in inflammation and cancer. Inflammation is associated with NF-κB activation, which can have dual roles in cancer by promoting immune defense or contributing to tumor progression. NF-κB is constitutively active in many cancers and can promote tumor growth by upregulating anti-apoptotic genes and other pro-tumorigenic functions. It also influences immune responses and cancer cell survival. NF-κB signaling interacts with other transcription factors like STAT3, p53, and ERG, as well as signaling pathways such as those involving GSK3-β, MAPK, and miRNAs. These interactions are crucial for regulating gene expression and cellular processes. NF-κB is a target for drug combination therapies in cancer, where its inhibition can enhance the effectiveness of chemotherapy and radiotherapy by reducing tumor cell survival and promoting immune responses. Overall, NF-κB plays a central role in inflammation, stress response, and cancer, with complex interactions that influence its activity and function in various cellular contexts.NF-κB is a key transcription factor involved in inflammation and innate immunity, and increasingly recognized as crucial in cancer initiation and progression. It interacts with various signaling molecules and pathways, including other transcription factors like STAT3, p53, and ERG, as well as kinases such as GSK3-β, p38, and PI3K. These interactions can either directly affect NF-κB subunits or influence its target genes. Other molecules, such as reactive oxygen species and miRNAs, also play roles in crosstalk with NF-κB. The complexity of NF-κB signaling is further increased by differential DNA-binding preferences of different dimers and post-translational modifications that affect its activity and interactions with other pathways. NF-κB signaling is activated through various pathways, including canonical, non-canonical, and atypical routes, each with distinct mechanisms and roles in inflammation and cancer. Inflammation is associated with NF-κB activation, which can have dual roles in cancer by promoting immune defense or contributing to tumor progression. NF-κB is constitutively active in many cancers and can promote tumor growth by upregulating anti-apoptotic genes and other pro-tumorigenic functions. It also influences immune responses and cancer cell survival. NF-κB signaling interacts with other transcription factors like STAT3, p53, and ERG, as well as signaling pathways such as those involving GSK3-β, MAPK, and miRNAs. These interactions are crucial for regulating gene expression and cellular processes. NF-κB is a target for drug combination therapies in cancer, where its inhibition can enhance the effectiveness of chemotherapy and radiotherapy by reducing tumor cell survival and promoting immune responses. Overall, NF-κB plays a central role in inflammation, stress response, and cancer, with complex interactions that influence its activity and function in various cellular contexts.