Integrated bioinformatics analysis reveals convergent molecular signatures associated with SERPINB7 and SERPINA12 deficiency.

BACKGROUND: Pathogenic variants in SERPINA12 have recently been identified in patients with palmoplantar keratoderma (PPK). Clinically, SERPINA12-associated PPK shares substantial overlap with Nagashima-type palmoplantar keratoderma (NPPK) caused by SERPINB7 deficiency, although inflammatory manifestations appear to be more prominent in SERPINA12-associated disease. The molecular basis underlying these similarities and differences remains unclear. METHODS: Virtual knockout analyses of SERPINA12 and SERPINB7 were performed using the scTenifoldKnk framework. Functional enrichment analyses, including GO, KEGG, and GSEA, were conducted to characterize perturbed biological pathways. Correlation analyses were performed using extracellular matrix (ECM)- and inflammation-related gene signatures. In addition, SERPINA12 was overexpressed in TNF-α-stimulated HaCaT keratinocytes to evaluate its effects on inflammatory cytokine expression. RESULTS: Both SERPINA12 and SERPINB7 were associated with ECM-related biological processes and pathways, suggesting a potential shared role in extracellular matrix homeostasis. However, SERPINA12 deficiency preferentially perturbed immune- and inflammation-related pathways, including Toll-like receptor signaling, interleukin signaling, and leukocyte activation. Consistently, SERPINA12 overexpression significantly reduced TNF-α, IL-8, and IL-1β expression in TNF-α-stimulated HaCaT cells. CONCLUSION: SERPINA12 and SERPINB7 are associated with extracellular matrix-associated functions that may account for their similar keratoderma phenotypes. In contrast, SERPINA12 additionally may exerts anti-inflammatory effects, providing a potential molecular explanation for the enhanced inflammatory manifestations observed in SERPINA12-associated PPK.