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

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.