Identifying novel risk targets in inflammatory skin diseases by comprehensive proteome-wide Mendelian randomization study

Abstract Background Despite advances in cancer biomarkers and targeted therapies, early diagnosis and treatment of inflammatory skin diseases remain challenging. This study aims to identify circulating proteins causally linked to inflammatory skin diseases, including acne, atopic dermatitis, systemic lupus erythematosus, psoriasis, rosacea, and urticaria, through a Mendelian randomization (MR) framework. Methods A large-scale MR analysis was performed to assess the causal effects of thousands of plasma proteins on common inflammatory skin diseases. Additional methods, including Steiger filtering, transcriptome-wide association studies, summary data–based MR, protein–protein interaction networks, pathway enrichment analyses, Bayesian colocalization, and drug target evaluation, were employed to validate MR findings and explore therapeutic targets. Results This study identified >100 circulating proteins that may be involved in inflammatory skin diseases. Tier 1 therapeutic targets include RARRES2, SERPINC1, GALK1, and ECM1 for atopic dermatitis and RARRES2, PPID, and IL1RL1 for acne, rosacea, and urticaria. These proteins represent promising avenues for developing new treatments, with the potential to improve diagnostics and therapeutic strategies in the future. Conclusion This MR analysis revealed numerous plasma proteins associated with inflammatory skin diseases, offering insights into protein-mediated mechanisms and highlighting promising therapeutic targets for future interventions. Key message What is already known on this topic Inflammatory skin diseases, including psoriasis, atopic dermatitis, and acne, are complex conditions linked to systemic factors such as alterations in circulating plasma proteins. Previous studies have identified certain proteins involved in skin immune responses; however, a comprehensive understanding of their causal roles remains lacking. What this study adds This study utilized a large-scale proteome-wide Mendelian randomization analysis to identify >100 circulating proteins causally linked to inflammatory skin diseases. Notably, proteins such as RARRES2, SERPINC1, and ECM1 were highlighted as potential therapeutic targets for atopic dermatitis and acne, among others. How this study might affect research, practice, or policy The findings provide novel insights into protein-mediated mechanisms underlying inflammatory skin diseases, suggesting new diagnostic and therapeutic avenues. Future research should focus on validating these protein targets in clinical settings and exploring their potential for therapeutic intervention.