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

The molecular regulators driving melanoma pathogenesis remain incompletely defined. Although plasma proteins show associations with melanoma, their causal relationships are unclear.

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.

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.

In conclusion, our results demonstrate that PARP1 is a key driver of melanoma pathogenesis and represents a potential specific molecular target for therapeutic intervention.