NF-κB in biology and targeted therapy:new insights and translational implications

NF-κB signaling has been discovered for nearly 40 years.Initially,NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses.However,with extensive and in-depth investigations,researchers have discovered that its role can be expanded to a variety of signaling mechanisms,biological processes,human diseases,and treatment options.In this review,we first scrutinize the research process of NF-κB signaling,and summarize the composition,activation,and regulatory mechanism of NF-κB signaling.We investigate the interaction of NF-κB signaling with other important pathways,including PI3K/AKT,MAPK,JAK-STAT,TGF-β,Wnt,Notch,Hedgehog,and TLR signaling.The physiological and pathological states of NF-κB signaling,as well as its intricate involvement in inflammation,immune regulation,and tumor microenvironment,are also explicated.Additionally,we illustrate how NF-κB signaling is involved in a variety of human diseases,including cancers,inflammatory and autoimmune diseases,cardiovascular diseases,metabolic diseases,neurological diseases,and covID-19.Further,we discuss the therapeutic approaches targeting NF-κB signaling,including IKK inhibitors,monoclonal antibodies,proteasome inhibitors,nuclear translocation inhibitors,DNA binding inhibitors,TKls,non-coding RNAs,immunotherapy,and CAR-T.Finally,we provide an outlook for research in the field of NF-κB signaling.We hope to present a stereoscopic,comprehensive NF-κB signaling that will inform future research and clinical practice.