ORIGINAL RESEARCH article
Front. Genet.
Sec. Applied Genetic Epidemiology
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1657356
This article is part of the Research TopicGenetics and Epigenetics of Melanoma and Non-Melanoma Skin CancerView all 7 articles
Identification of druggable targets in melanoma by multi-omics Mendelian randomization integrated with transcriptomic and spatial analysis
Provisionally accepted
- 1Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- 21st Medical Center of Chinese PLA General Hospital, Beijing, China
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Background: Cutaneous melanoma (CM) is a highly lethal skin tumor. Some patients respond poorly to existing therapies, and developing new targeted therapies remains challenging. Methods: 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. Results: 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. Conclusion: This study provides robust genetic and therapeutic evidence for targeting EPS15L1 and HGS in CM treatment. Keywords: Melanoma, Mendelian randomization, Multi-omics, Drug repositioning.
Keywords: Melanoma, Mendelian randomization, multi-omics, Drug Repositioning, Bioinforamtics
Received: 02 Jul 2025; Accepted: 14 Oct 2025.
Copyright: © 2025 Xing, Yang, Chen and Tao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ran Tao, taoran301prs@163.com
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