# Identification of druggable targets in melanoma by multi-omics Mendelian randomization integrated with transcriptomic and spatial analysis

## TL;DR

This study identifies two genes, EPS15L1 and HGS, as potential drug targets for melanoma treatment using genetic and multi-omics analyses.

## Contribution

The novel contribution is the integration of multi-omics MR with spatial and transcriptomic analysis to identify and validate druggable targets in melanoma.

## Key findings

- EPS15L1 and HGS gene levels are associated with increased melanoma risk.
- Multi-omics analysis revealed interactions between EPS15L1 and HGS with doxorubicin.
- Molecular experiments confirmed the validity of EPS15L1 and HGS as therapeutic targets.

## Abstract

Cutaneous melanoma (CM) is a highly lethal skin tumor. Some patients respond poorly to existing therapies, and developing new targeted therapies remains challenging.

We combined the results of eQTLs, pQTLs, and genome-wide association study (GWAS) to identify potential causal effects of two target genes on CM, based on multi-omics Mendelian randomization (MR). Sensitivity analysis, co-localization analysis, and inverse MR analysis were also employed to verify the robustness of this causal relationship. Multi-omics data were then applied to explore the expression patterns of immune infiltration of the target genes and construct nomogram models.

The results showed that the gene prediction levels of EPS15L1 and HGS were associated with an increased risk of CM. Co-localization analysis revealed significant horizontal pleiotropy of the target gene, and reverse MR showed unidirectional causality of the targets. Multi-omics analysis comprehensively demonstrated the expression regulation pattern of the target genes in the CM immune-environment and identified interactions between EPS15L1 (Q9UBC2) and HGS (O14964) and doxorubicin, demonstrating the potential for drug application. The validity of the targets was further verified by molecular biology experiments.

This study provides robust genetic and therapeutic evidence for targeting EPS15L1 and HGS in CM treatment.