NF-κB-c-Rel in psoriasis: genetic susceptibility, immunopathogenic circuits, and emerging therapeutic opportunities
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.