Unveiling the Mechanism of Retinoic Acid Therapy for Cutaneous Warts: Insights from Multi-Omics Integration

Abstract

Background: Due to limited treatment options, cutaneous warts caused by human papillomavirus (HPV) remain a significant clinical challenge. Furthermore, the genetic susceptibility and molecular basis of viral warts are not yet fully understood.

Methods: We utilized a multi-omics integration approach, encompassing genome-wide association study (GWAS) meta-analysis, summary data-based Mendelian randomization (SMR) analysis, and transcriptomic validation using the GSE136347 dataset. Differential gene expression (DEG) analysis was conducted to identify significant changes in gene expression between wart tissues and healthy skin.

Results: Our analyses revealed five genetic susceptibility genes associated with cutaneous warts, with RARA showing significant differential expression in wart tissues. Co-expression analysis indicated that RARA may regulate apoptosis through interactions with BAX, a pro-apoptotic gene. Additionally, functional annotation via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses highlighted key biological processes and pathways involved in wart pathogenesis.

Conclusion: This study identifies RARA as a pivotal regulator in the molecular pathology of cutaneous warts and a promising therapeutic target. RA-based therapies could offer effective and less invasive alternatives for wart treatment. Future investigations should refine the molecular role of RARA to optimize clinical interventions.

Keywords: GWAS-meta; RARA; cutaneous warts; multi-omics; retinoic acid.

Figure 1

Study design overview.

Figure 2

(A) Results of SMR analysis based on the eQTLgen database, identifying genes with a significant association with warts. Yellow bars indicate genes with a positive beta value (Beta > 0), suggesting a potential positive association with disease progression, while blue bars represent genes with a negative beta value (Beta < 0), indicating a potential inhibitory role in disease progression. (B) Results of SMR analysis based on the GTEx database, further validating five genes with significant associations. Similarly, yellow bars denote genes with positive beta values, implying potential promotive effects on disease, while blue bars represent genes with negative beta values, indicating potential suppressive effects. (C) Final selection of 5 genetic susceptibility genes for warts after multi-step filtering through integrated analysis of eQTLgen and GTEx databases, highlighting the robustness of these candidates. (D) Genomic distribution of the 5 identified genetic susceptibility genes, visualized across the genome to illustrate their locations on different chromosomes, providing a comprehensive view of their genetic context.

Figure 3

(A) Violin plot illustrating RARA expression levels in wart tissue compared to control samples, further confirming its differential expression and potential involvement in wart pathogenesis. The widened areas of the plot indicate higher sample density, providing a clear view of expression variability. *** indicates P < 0.001, representing results with extremely significant statistical difference. (B) Co-expression analysis stratified by median RARA expression, showing increased BAX expression in the high-RARA group. This suggests a potential mechanistic link between RARA and apoptosis-related genes, which may contribute to the apoptotic clearance of HPV-infected cells. The stratification allows for a focused comparison of gene interactions within biologically relevant expression thresholds. (C) Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differentially expressed genes (DEGs) between high- and low-RARA expression groups. The analysis highlights enriched biological functions and pathways, including DNA metabolism, cell cycle regulation, transcriptional control, immune response, and viral infection pathways. These findings provide insights into the broader molecular context in which RARA functions, suggesting its potential roles in both host defense mechanisms and HPV-associated processes.