Integrative multi-omics analysis prioritizes DPEP1 as a genetically supported candidate associated with skin cancer risk

Abstract

Background: Skin cancer (SC) is among the most prevalent malignancies, yet causal circulating proteins and tractable therapeutic targets remain poorly defined.

Methods: We performed a proteome-wide Mendelian randomization (MR) analysis of 4972 proteins across large GWAS datasets (discovery: 23 694 cases and 372 016 controls; replication cohorts: > 42 000 cases and > 810 000 controls). Sensitivity analyses, bidirectional MR, Steiger filtering and SMR testing supported robustness. Based on an integrated prioritization framework, DPEP1 was selected for downstream analyses. We then explored DPEP1-associated transcriptional programs using bulk and single-cell transcriptomic datasets and performed virtual screening, docking and molecular dynamics (MD) simulations to prioritize candidate DPEP1-binding ligands for future validation.

Results: MR identified six genetically supported proteins associated with SC risk, and DPEP1 was prioritized for downstream characterization based on an explicit target-prioritization framework. In the murine Dpep1-knockout dataset, Dpep1 deficiency was associated with altered stromal and immune programs, including reduced fibroblast abundance, lower YAP-TEAD/TGF-β pathway activity and increased CD8⁺ T-cell cytotoxicity scores. In human melanoma single-cell analyses, DPEP1 expression was enriched in fibroblasts and inferred ligand–receptor analyses suggested potential communication between DPEP1⁺ ·fibroblasts and immune subsets, including CXCL12–CXCR4 and MIF–CD74/CXCR4 interactions. Structure-based screening identified Balsaminone B as a top-ranked predicted high-affinity ligand, supported by stable docking and MD trajectories, with additional candidates including Ergotamine, Evobioside, MOL012579 and Venetoclax.

Conclusion: Together, these findings prioritize DPEP1 as a genetically supported candidate associated with skin cancer risk and provide supportive transcriptomic and computational evidence for future mechanistic and therapeutic investigation.

Keywords

DPEP1 / Mendelian randomization / molecular docking / skin cancer / tumour microenvironment

References

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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.