Proliferation-associated protein 2G4 promotes keratinocyte proliferation and survival in psoriasis

BACKGROUND: Psoriasis is a noncommunicable inflammatory skin disease that affects approximately 2-3% of the world's population. Given its high impact on quality of life and the fact that a subset of patients exhibits suboptimal or secondary loss of response to current treatments, identifying new therapeutic strategies is crucial. Proliferation-associated protein 2G4 (PA2G4) is a transcription factor that has been exclusively studied in cancer research, where it promotes cell growth and enhances tumorigenesis by inhibiting apoptosis. However, its role in inflammatory skin diseases remains largely unknown. OBJECTIVES: To elucidate the pathophysiological and immunological functions of PA2G4 in psoriasis, and to evaluate its potential as a therapeutic target. METHODS: Bulk, single-cell and spatial RNA sequencing (RNAseq) combined with immunohistochemistry were used to assess PA2G4 expression in psoriatic skin compared with nonlesional control samples. Functional studies were performed in primary human keratinocytes and reconstructed human epidermis (RHE) models using the CRISPR/Cas9-mediated knockout of PA2G4 and pharmacological inhibition of PA2G4 with the small-molecule inhibitor WS6. The regulatory effects of PA2G4 on cellular processes, such as proliferation, differentiation and survival, were investigated using RNAseq, Western blot analysis, scratch assays and annexin V staining. RESULTS: PA2G4 was highly abundant in psoriasis, and its expression was predominantly restricted to basal proliferating keratinocytes. Its expression was positively correlated with psoriasis severity, the degree of acanthosis, neutrophil infiltration and genes that are upregulated in psoriasis. PA2G4 knockout in primary human keratinocytes activated differentiation pathways while suppressing proliferation pathways, resulting in the downregulation of proliferation- and inflammation-related genes (e.g. MKI67, IL20, VEGFA and HIF1A) and the upregulation of differentiation and cell adhesion markers (e.g. KRT6C, LCE2C and DSG4). Functionally, PA2G4 knockout reduced keratinocyte proliferation in scratch assays, attenuated interleukin-22-induced acanthosis in RHE models and promoted keratinocyte death. Pharmacological inhibition of PA2G4 using the small-molecule inhibitor WS6 similarly downregulated genes associated with proliferation and cell survival. CONCLUSIONS: PA2G4 could promote keratinocyte hyperproliferation and survival in psoriasis, thereby critically influencing epidermal homeostasis. Therefore, inhibition of PA2G4 may represent a new treatment option for psoriasis.