Genomics-informed drug-repurposing strategy identifies two therapeutic targets for preventing liver disease associated with metabolic dysfunction

作者：Hannah M. Seagle, Alexis T. Akerele, Joseph A. DeCorte, Jacklyn N. Hellwege, Joseph H. Breeyear, Jeewoo Kim, Michael G. Levin, Samuel Khodursky, Adam P. Bress, Kyung Min Lee, Jens Meiler, Dipender Gill, Jennifer S. Lee, Kent Heberer, Donald R. Miller, Peter D. Reaven, Kyong‐Mi Chang, Julie A. Lynch, Nikhil K. Khankari, Megan M. Shuey, Todd L. Edwards, Marijana Vujković · 发表于：The American Journal of Human Genetics · 年份：2025 · DOI：10.1016/j.ajhg.2025.06.014 · 被引用次数：2 · 研究领域：Liver Disease Diagnosis and Treatment、Genetic Associations and Epidemiology、Lipid metabolism and disorders

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention.