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NF-κB-c-Rel in psoriasis: genetic susceptibility, immunopathogenic circuits, and emerging therapeutic opportunities
Ruiling Liu1,2, Yujie Wu1,2, Wenjing Jia1,2
1Joint National Laboratory for Antibody Drug Engineering, Henan University School of Medicine, Kaifeng, China.
Abstract:
Psoriasis is a chronic, relapsing, immune-mediated inflammatory dermatosis characterized by aberrant keratinocyte hyperproliferation and prominent infiltration of inflammatory leukocytes. Among the NF-κB transcription factor family, c-Rel is the first member conclusively implicated as a psoriasis susceptibility gene, and its dysregulated expression positively correlates with clinical disease activity. Mechanistically, c-Rel orchestrates pathogenic inflammation by coordinating immune-cell differentiation programs and inflammatory cytokine production, while also contributing to keratinocyte proliferation and inflammatory responses in non-hematopoietic compartments. Emerging therapeutic approaches that modulate c-Rel, ranging from biologics and small-molecule inhibitors to nucleic-acid-based interventions, have shown encouraging efficacy in both clinical study and experimental psoriasis models. However, key translational hurdles remain, including suboptimal delivery, incomplete target-cell specificity, and long-term safety concerns. Deeper delineation of upstream activation cues and cell-type-restricted c-Rel regulatory circuits will be essential to enable precision targeting of c-Rel in psoriasis.
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