PU.1 drives psoriasis pathogenesis by promoting intermediate monocytes-to-M1 macrophage differentiation through...

The expansion and pathogenic differentiation of intermediate monocytes (IMs) are critical yet poorly understood events in psoriasis pathogenesis. Here, we identify the transcription factor PU.1 (encoded by SPI1) as a master regulator driving IM-mediated psoriasiform inflammation. Single-cell RNA sequencing and flow cytometry of peripheral blood mononuclear cells revealed expansion of IMs in psoriasis patients, with PU.1 uncovered as its specific regulator. Myeloid-specific ablation of Spi1 in mice ameliorated imiquimod-induced psoriasiform dermatitis. Mechanistically, PU.1 promoted IMs differentiation into pro-inflammatory M1 macrophages by transcriptionally upregulating Dectin-1, thereby activating the SYK/NF-κB pathway. We further discovered that the clinical-stage bromodomain and extra-terminal domain inhibitor NHWD-870 effectively suppressed PU.1 expression. Oral administration of NHWD-870 demonstrated potent efficacy in murine psoriasis models by disrupting this PU.1-dependent IMs differentiation. Our findings establish PU.1 as a novel therapeutic target for psoriasis and propose that pharmacologic inhibition of PU.1 represents a promising treatment strategy.