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Publications

Journal Article Epublish

PubMed: 40399559 DOI: 10.1038/s42003-025-07860-z

Genetic insights support PARP1 as a mediator in the protective association of ATP-citrate lyase inhibitors with melanoma.

Commun Biol 8(1):777

Authors: Jiawen Lu, Gloria Hoi-Yee Li, Jingyi Hu, Zhenqian Wang

Affiliations

  • Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, China. School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.
  • Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, China.
  • National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.
  • Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, China. School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.

Abstract

ATP-citrate lyase (ACLY) inhibitors emerge as a promising anti-cancer strategy, yet their causal effects across various cancer types remain unclear. Here, we employ a drug-target Mendelian randomization (MR) approach using four cis-expression quantitative trait loci for blood ACLY gene expression as genetic instruments to mimic ACLY inhibition. We utilize genetic data from the eQTLGen consortium (N = 31,684) for ACLY expression, the deCODE study (N = 35,559) for plasma proteome, and large-scale cancer genome-wide association studies consortia (N from 49,708 to 417,127) to investigate the association of genetically mimicked ACLY inhibitors with 17 cancers and identify potential mediating proteins. Genetically proxied ACLY inhibition is strongly associated with reduced melanoma risk (odds ratio [95% confidence interval (CI)]: 0.85 [0.78, 0.92]) in a combined analysis of two independent outcome datasets. Proteome-wide MR screening 1517 plasma proteins identifies 3 proteins associated with melanoma, with Poly [ADP-ribose] polymerase 1 (PARP1) showing strong colocalization support. Mediation analysis further suggests PARP1 as a mediator in the protective effect of ACLY inhibition on melanoma (mediated proportion [95% CI]: 51.52% [5.45%, 97.58%]). Follow-up and validation analyses support the robustness of these results. This study illuminates the therapeutic potential of ACLY inhibition in melanoma, with PARP1 implicated as a potential mediator, offering avenues for targeted interventions.

MeSH

Genes, Poly(Adp-Ribose) Polymerases, Atp Citrate (Pro-S)-Lyase, Biological Science Disciplines, Melanoma, Neoplasms, Poly Adenosine Diphosphate Ribose, Lyases, Plasma