The article "NF-κB, the first quarter-century: remarkable progress and outstanding questions" by Matthew S. Hayden and Sankar Ghosh reviews the past 25 years of research on NF-κB, a key transcription factor involved in immune responses and various diseases. NF-κB plays a central role in the immune system and is crucial for cell survival, differentiation, and proliferation. It is activated by various stimuli, including inflammatory signals, and its dysregulation is linked to diseases such as cancer, autoimmune disorders, and metabolic diseases. The article highlights significant progress in understanding the mechanisms of NF-κB regulation, including the role of the IKK complex, IκB proteins, and the NF-κB dimers. Despite these advances, many fundamental questions remain unanswered, particularly regarding the precise mechanisms of IKK activation, the role of ubiquitination in signaling, and the regulation of NF-κB in different physiological contexts. The article also discusses the importance of NF-κB in linking physiological processes to pathological conditions, such as inflammation and cancer. Overall, the review underscores the complexity of NF-κB signaling and the need for further research to fully understand its role in health and disease.The article "NF-κB, the first quarter-century: remarkable progress and outstanding questions" by Matthew S. Hayden and Sankar Ghosh reviews the past 25 years of research on NF-κB, a key transcription factor involved in immune responses and various diseases. NF-κB plays a central role in the immune system and is crucial for cell survival, differentiation, and proliferation. It is activated by various stimuli, including inflammatory signals, and its dysregulation is linked to diseases such as cancer, autoimmune disorders, and metabolic diseases. The article highlights significant progress in understanding the mechanisms of NF-κB regulation, including the role of the IKK complex, IκB proteins, and the NF-κB dimers. Despite these advances, many fundamental questions remain unanswered, particularly regarding the precise mechanisms of IKK activation, the role of ubiquitination in signaling, and the regulation of NF-κB in different physiological contexts. The article also discusses the importance of NF-κB in linking physiological processes to pathological conditions, such as inflammation and cancer. Overall, the review underscores the complexity of NF-κB signaling and the need for further research to fully understand its role in health and disease.