FOSL1-associated condensates modulate superenhancer-mediated selected IL-1 family gene activation in psoriasis

Psoriasis is a chronic inflammatory skin disease involving abnormal keratinocyte gene expression, yet the upstream epigenetic mechanisms driving these alterations remain unclear. Here we performed multiomics analyses (chromatin immunoprecipitation sequencing, CUT&Tag, ATAC-seq, and RNA sequencing) on psoriatic lesions, perilesional skin, healthy skin, and M5-stimulated HaCaT cells. Functional validation was performed using CRISPR-mediated superenhancer (SE) editing, epigenetic modulation, circular chromosome conformation capture sequencing, assay for chromatin-bound condensates by exploratory sequencing, coimmunoprecipitation, and fluorescence recovery after photobleaching. We found widespread activation of enhancers and SEs in lesions, including an interleukin 1 (IL-1)–SE regulating IL1A , IL1B , and IL36G transcription. BET inhibition reduced SE activity, repressed IL-1 cytokines, and relieved psoriasis-like inflammation in vivo. Fos-like antigen 1 (FOSL1) was identified as a key transcription factor enriched in active SEs and associated with condensate formation, contributing to the maintenance of EP300 occupancy and histone H3 lysine 27 acetylation deposition. Macrophage-derived IL-1 up-regulated FOSL1 through mitogen-activated protein kinase/ERK signaling, forming a positive feedback loop that amplified inflammation. This study revealed an FOSL1-SE–centered regulatory network driving keratinocyte inflammatory responses, providing previously unknown therapeutic targets for psoriasis.