Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Acute radiation exposure usually causes severe dysfunction in various tissues of the organism, among which hematopoiesis, digestion, skin, cardiovascular and nervous system are most obviously affected, often leading to extensive apoptosis and acute radiation syndrome. Apoptosis inhibition or loss could increase proliferation of tumor cells through p53 and NF-κB pathways. Toll-like receptors ( TLRs) are a class of protein molecules involved in non-specific immunity. Up-regulation of the NF-κB pathway results in a significant increase in the radioresistance of cells. TLR4 has a basal cell radiation damage protection effect. Traditional TLR4 agonist lipopolysaccharide is limited in clinical application due to severe toxicity. Recently, some new TLRs agonists have been reported, which have protective effects against the lethal effects of ionizing radiation and lower toxic side effects. Among them, TLR2, TLR4, TLR5 and TLR9 play key roles in radiation protection, such as TLR2 receptor agonist bacterial lipoprotein (BLP), TLR4 receptor agonist heat-activated Salmonella typhimurium (HKST), TLR5 receptor agonism Bacterial flagellin and TLR9 receptor agonist. However, those different TLRs recognize specific components of the pathogen and thus initiate different downstream signaling pathways with different protective effects.