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To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high\u2010throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements\u2010cytoscape, and bioinformatic analyses employing Advaita\u00ae iPathwayGuide and DisGeNET for identification of disease\u2010related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real\u2010time polymerase chain reaction assay. Our systematic analysis of androgen deprivation\u2010associated genes involved multiple biological processes, including neuroactive ligand\u2013receptor interaction, axon guidance, cytokine\u2013cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma\u2010aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein\u2013protein interaction network analysis highlighted the role of ligand\u2010gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene\u2013disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type\u20101 angiotensin II receptor, brain\u2010derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N\u2010methyl\u2010D\u2010aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5\u2010hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT\u2010mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.<\/jats:p>","DOI":"10.1002\/mc.23708","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T11:54:36Z","timestamp":1710417276000},"page":"1051-1063","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ligand\u2010gated ion channels as potential biomarkers for ADT\u2010mediated cognitive decline in prostate cancer patients"],"prefix":"10.1002","volume":"63","author":[{"given":"Shiv","family":"Verma","sequence":"first","affiliation":[{"name":"Department of Urology, School of Medicine Case Western Reserve University Cleveland Ohio USA"},{"name":"The Urology Institute University Hospitals Cleveland Medical Center Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vaibhav","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine 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