Mendelian Randomization Unveils Poly(ADP-ribose) Polymerase 1 as Causal Plasma Protein Target in Melanoma, Integrated Multi-omics.

Background: The molecular regulators driving melanoma pathogenesis remain incompletely defined. Although plasma proteins show associations with melanoma, their causal relationships are unclear. Methods: We performed Mendelian randomization (MR) using proteomic data from the UK Biobank Pharma Proteomics Project and deCODE genetics to identify plasma proteins causally linked to melanoma. Colocalization, summary data-based MR, heterogeneity in dependent instruments, and MR-phenome-wide association study analyses identified druggable targets. Transcriptome profiling of melanoma tissues and single-cell functional validation assessed the target roles. Results: Poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) was established as a causal risk factor and druggable target for melanoma. Elevated PARP1 expression in melanoma tissues correlated with poor patient survival. Functional analyses revealed that PARP1 coordinates protumorigenic functions with cell-specific roles. Conclusions: In conclusion, our results demonstrate that PARP1 is a key driver of melanoma pathogenesis and represents a potential specific molecular target for therapeutic intervention.