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.

Objective To investigate the expression of peripheral programmed death (PD)-1hiCXCR5-CD4+T cells and its clinical significance in systemic lupus erythematosus (SLE). Methods Peripheral blood PD-1hiCXCR5-CD4+ T cells from 21 SLE patients and 16 healthy controls were examined by flow cytometry. The levels of serum anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies were determined using immunoradiometric as-say. Data were analyzed with t test and Pearson's correlation test. Results The per-centages of PD-1hiCXCR5- cells within CD4+ T cell were significantly higher in SLE patients [(2.1 ±2.0)％] compared to normal controls [(0.3±0.3)％] (t=2.959, P<0.01). The percentages of PD-1hiCXCR5-cells within CD4+T cells in moderate to severe active SLE patients (3.0 ±2.0)％ was significantly increased compared to patients with mild or inactive (1.0±1.4)％(t=2.574, P<0.05) and normal controls (0.3±0.3)％ (t=5.149, P<0.01). The percentages of PD-1hiCXCR5- cells within CD4+ T cells from SLE patients were positively related with systemic lupus erythematosus disease activity index (SLEDAI) (r=0.475, P=0.0297). SLE patients in serum anti-dsDNA antibodies positive group (2.7±2.1)％displayed a higher percentage of PD-1hiCXCR5-cells within CD4+T cells than patients in serum anti-dsDNA antibodies negative group (0.6 ±0.5)％ (t=2.303, P<0.05). The percentages of PD-1hiCXCR5-cells within CD4+T cells from SLE patients were positively correlated with anti-dsDNA antibody titers. Conclusion The percentages of PD-1hiCXCR5- cells within CD4+ T cells from SLE patients are increased and are positively correlated with SLEDAI and anti-dsDNA antibody levels. Increased percentage of PD-1hiCXCR5-cells within CD4+T cells might play an important role in the pathogenesis of SLE.