Psoriasis-risk SNP rs610604 reveals nuclear IKKα-TNFAIP3 repressor axis driving autoinflammatory circuits

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune activation. The SNP rs610604 within the TNFAIP3 locus is associated with increased psoriasis susceptibility and response to TNF-targeted therapies, yet its functional mechanism remains unclear. In this study, we identify, to our knowledge, a previously unreported regulatory axis linking IKKα to TNFAIP3 in keratinocytes and demonstrate how genetic variation at rs610604 modulates inflammatory signaling. Genome-wide chromatin profiling revealed that nuclear IKKα predominantly occupies transcriptionally inactive regions and acts as a chromatin-associated repressor. Among its targets, TNFAIP3 emerged as a key locus containing an IKKα-binding region overlapping the rs610604 variant. Functional analyses showed allele-specific recruitment of IKKα, with the psoriasis-risk G allele displaying stronger and more persistent binding than the protective T allele. This interaction promotes transcriptional repression of TNFAIP3, a negative regulator of NF-κB, MAPK, and IL-17 pathways, thereby sustaining proinflammatory signaling; consistently, in psoriatic lesions, nuclear IKKα is reduced. These findings identify a nuclear IKKα-TNFAIP3 axis linking genetic susceptibility to inflammatory signaling, providing a potential explanation for the paradox of chronic inflammation without frequent malignant transformation in psoriatic skin and highlighting IKKα as a potential therapeutic target in psoriasis and related inflammatory disorders.