PROLIFERATION-ASSOCIATED protein 2G4 (PA2G4) has been identified as a key driver of keratinocyte overgrowth and survival in psoriasis, highlighting a promising new target for treatment.
Psoriasis, a chronic inflammatory skin condition affecting approximately 2–3% of the global population, is characterised by excessive keratinocyte proliferation and impaired differentiation. While current therapies have improved disease management, a subset of patients experience inadequate response or loss of efficacy over time, underscoring the need for novel therapeutic strategies.
Study Highlights PA2G4 Role in Psoriasis Progression
In this study, researchers investigated the role of PA2G4, a transcription factor previously studied primarily in cancer biology, where it is known to promote cell growth and inhibit apoptosis. Using a combination of bulk, single-cell, and spatial RNA sequencing alongside immunohistochemistry, the researchers found that PA2G4 expression was significantly elevated in psoriatic skin compared with non-lesional controls. Notably, its expression was largely confined to basal keratinocytes, the primary proliferating cells in the epidermis.
Importantly, PA2G4 levels were positively correlated with disease severity, epidermal thickening (acanthosis), neutrophil infiltration, and the expression of genes associated with psoriasis pathology. These findings suggest a central role for PA2G4 in driving disease activity.
Functional experiments provided further insight. Using CRISPR/Cas9-mediated knockout of PA2G4 in primary human keratinocytes, researchers observed a shift from proliferation towards differentiation. This was accompanied by reduced expression of proliferation- and inflammation-related genes, including MKI67, IL20, VEGFA, and HIF1A, alongside increased expression of differentiation markers.
In laboratory models, loss of PA2G4 reduced keratinocyte proliferation, limited inflammation-induced epidermal thickening, and increased cell death. Similarly, pharmacological inhibition using the small molecule WS6 replicated these effects, suppressing pathways linked to cell growth and survival.
Clinical Potential of PA2G4 Targeting in Psoriasis
Together, these findings position PA2G4 as a critical regulator of epidermal homeostasis in psoriasis. Targeting this protein could offer a novel therapeutic approach aimed at restoring the balance between keratinocyte proliferation and differentiation.
Further research is needed to validate these findings in clinical settings, but the study provides a strong foundation for the development of PA2G4-targeted therapies in psoriasis.
Reference
Raunegger T et al. Proliferation-associated protein 2G4 promotes keratinocyte proliferation and survival in psoriasis. Br J Dermatol. 2026;DOI: 10.1093/bjd/ljag154.
Featured image: Ольга Тернавская on Adobe Stock
