Downregulation of SPRED1 drives keratinocyte hyperproliferation in psoriasis via activation of the ERK-RSK1 signaling axis

Psoriasis features excessive epidermal keratinocyte proliferation, and our previous work identified a non-synonymous mutation in SPRED1 in psoriasis, specifically an enrichment of c.A881T (p.Y294F) in exon 7 (chr15:38351210). Combining public database data and clinical skin specimens, this study confirmed reduced SPRED1 expression in psoriatic lesions. Functional investigations were performed using HaCaT/NHEK keratinocyte transfection models, imiquimod-induced psoriasis-like mouse models, pathway agonist/inhibitor rescue assays, co-immunoprecipitation and dual-luciferase detection. SPRED1 indirectly interacts with nuclear ERK to block ERK-RSK1 activation and restrain keratinocyte overgrowth, whereas miR-126 downregulates SPRED1 by direct targeting. Intradermal supplementation of recombinant SPRED1 alleviates skin pathological changes in mice. These findings define the miR-126/SPRED1/ERK-RSK1 regulatory cascade and support SPRED1 as a promising candidate target for psoriasis treatment.