{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:45:31Z","timestamp":1788975931656,"version":"build-2803163510"},"reference-count":105,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the National Center for Advancing Translational Sciences (NCATS)","award":["#NTR 12003"],"award-info":[{"award-number":["#NTR 12003"]}]},{"name":"National Institute of Environmental Health Sciences (NIEHS)\/Division of Translational Toxicology to the NCATS, National Institutes of Health (NIH)","award":["#NTR 12003"],"award-info":[{"award-number":["#NTR 12003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The kisspeptin\/kisspeptin receptor (KISS1\/KISS1R) system has emerged as a vital regulator of various physiological processes, including cancer progression, metabolic function, and reproduction. KISS1R, a member of the G protein-coupled receptor family, is crucial for regulating the hypothalamic\/pituitary\/gonadal axis. A growing number of KISS1R agonists are currently being investigated in clinical trials, whereas the number of antagonists remains limited. Most existing ligands are synthetic peptides, with only a few small-molecule compounds, such as musk ambrette, having been identified. In this article, we provide an overview of the KISS1\/KISS1R system and its involvement in diseases such as reproductive disorders, cancer, diabetes, and cardiovascular disease. We also highlight the various technologies used to identify KISS1R ligands, including radioligand binding assays, calcium flux assays, IP1 formation assays, ERK phosphorylation assays, qRT-PCR, and AI-based virtual screening. Furthermore, we discuss the latest advances in identifying KISS1R agonists and antagonists, highlighting ongoing challenges and future directions in research. These insights lay the groundwork for future research aimed at leveraging this system for developing innovative therapeutic strategies across a range of medical conditions.<\/jats:p>","DOI":"10.3390\/ijms26104890","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T06:10:46Z","timestamp":1747721446000},"page":"4890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Kisspeptin Receptor Agonists and Antagonists: Strategies for Discovery and Implications for Human Health and Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7435-8556","authenticated-orcid":false,"given":"Xing","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie D.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7285-8469","authenticated-orcid":false,"given":"Menghang","family":"Xia","sequence":"additional","affiliation":[{"name":"Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"34631","DOI":"10.1074\/jbc.M104847200","article-title":"The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54","volume":"276","author":"Kotani","year":"2001","journal-title":"J. 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