PSMA4 as a Druggable Target in Hidradenitis Suppurativa: Evidence From Mendelian Randomization and Single-Cell...

Area of Science:

• Genetics
• Immunology
• Dermatology

Background:

• Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with limited effective treatments.
• Drug resistance is common in HS, highlighting the urgent need for novel therapeutic targets.

Purpose of the Study:

• To identify druggable genetic targets for HS using a genome-wide Mendelian randomization (MR) analysis.
• To explore the functional roles and cell-type specificity of potential HS-associated genes.

Main Methods:

• Genome-wide Mendelian randomization (MR) analysis integrating cis-expression quantitative trait locus (eQTL) and HS genome-wide association study (GWAS) data.
• Colocalization, transcriptomic validation, single-cell RNA sequencing, and cell-cell communication analyses were employed.
• Statistical analysis prioritized PSMA4 and MAST3 based on significant associations and colocalization.

Main Results:

• Eight genes were significantly associated with HS via MR analysis.
• PSMA4 and MAST3 were prioritized as key druggable targets.
• PSMA4 was upregulated and MAST3 downregulated in HS lesions; PSMA4 is enriched in CD4+ T cells and linked to TNF signaling.

Conclusions:

• PSMA4 and MAST3 represent potential novel therapeutic targets for hidradenitis suppurativa.
• PSMA4 may drive HS inflammation through CD4+ T cell-mediated pathways, suggesting a new treatment strategy.