Downregulation of SPRED1 Drives Keratinocyte Hyperproliferation in Psoriasis via Activation of the ERK-RSK1 Signaling Axis

Psoriasis is a chronic inflammatory skin disease characterized by uncontrolled epidermal keratinocyte proliferation. Previous studies from our group identified a non-synonymous mutation in SPRED1 in psoriasis, specifically an enrichment of c.A881T (p.Y294F) in exon 7 (chr15:38351210). However, the mechanism by which SPRED1 regulates keratinocyte hyperproliferation in psoriasis remains undefined. To address this, we first validated SPRED1 expression in psoriatic lesions through both GEO database mining and clinical sample analysis. We then established SPRED1-overexpressing and SPRED1-knockdown keratinocyte models to characterize its functional role in psoriasis pathogenesis. Concurrently, we generated an imiquimod (IMQ)-induced psoriasis-like mouse model and a SPRED1-overexpression mouse model, using H&E staining, PCR, Western blot (WB), and tissue immunofluorescence to unveil in vivo mechanisms underlying SPRED1-mediated epidermal hyperproliferation. Rescue experiments were performed using the ERK agonist Ro67-7476 and ERK inhibitors PD98059/SCH772984 to dissect the ERK signaling pathway’s role in SPRED1-modulated keratinocyte viability and proliferation. Additionally, we constructed miR-126-overexpressing and miR-126-knockdown NHEK cell models to explore miR-126’s regulatory function in this context. Findings confirmed SPRED1 downregulation in psoriatic lesions via both bioinformatics and clinical validation. In vitro, SPRED1 overexpression inhibited keratinocyte proliferation by suppressing ERK phosphorylation, whereas SPRED1 knockdown promoted proliferation through enhanced ERK activation. In IMQ-induced mouse models, SPRED1 overexpression alleviated psoriatic skin lesions, demonstrating that SPRED1 upregulation suppresses epidermal hyperplasia in vivo. Co-immunoprecipitation further revealed that SPRED1 interacts indirectly with ERK within the nucleus to modulate cell viability and proliferation. Mechanistically, miR-126 was found to regulate keratinocyte proliferation by targeting SPRED1. Collectively, our results establish that SPRED1 downregulation drives keratinocyte hyperproliferation in psoriasis via ERK-RSK1 pathway activation, highlighting SPRED1 as a potential therapeutic target for psoriasis intervention.