{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:15:38Z","timestamp":1788344138255,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ghrelin regulates appetite, gastrointestinal motility and growth hormone (GH) secretion through activation of the growth hormone secretagogue receptor (GHSR\u20101a) in hypothalamic neurons, with downstream effects on adipose tissue and skeletal muscle. Although ghrelin and synthetic GHSR\u20101a agonists have been investigated for the treatment of anorexia, sarcopenia and cancer cachexia, their clinical utility has been limited by unfavourable pharmacokinetics. We recently discovered a novel class of small\u2010molecule compounds, termed KARIs, which act as potent GHSR\u20101a agonists with excellent brain permeability. Here, we evaluated their efficacy as GHSR\u20101a agonists in\u00a0vitro and in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>GHSR\u20101a agonistic effects of KARIs were assessed using calcium influx and competitive binding assays in human GHSR\u20101a\u2010expressing cells, and molecular docking simulations were conducted. Pharmacokinetic properties of KARIs (1\u2009mg\/kg i.v, 10\u2009mg\/kg p.o) were compared with anamorelin (3\u2009mg\/kg i.v., 30\u2009mg\/kg p.o.). In\u00a0vivo efficacy was evaluated in mouse models of postoperative ileus (POI; 10, 20 or 30\u2009mg\/kg), age\u2010related sarcopenia (10\u2009mg\/kg\/day for 4\u2009weeks) and cancer cachexia (10 or 30\u2009mg\/kg\/day from Days 9 to 24 after CT26 tumour induction).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      KARIs directly interacted with key GHSR\u20101a residues (Phe279) and increased calcium influx (EC\n                      <jats:sub>50<\/jats:sub>\n                      : KARI 101\u2009=\u20091.83\u2009\u00b1\u20091.05\u2009\u03bcM; KARI 201\u2009=\u20093.36\u2009\u00b1\u20091.09\u2009\u03bcM). KARIs showed higher oral bioavailability (BA: KARI 101\u2009=\u200963%; KARI 201\u2009=\u200968%) and brain distribution (KARI 101\u2009=\u20092.2; KARI 201\u2009=\u20093.7) than anamorelin (BA\u2009=\u200945%, brain distribution\u2009=\u20090.1). KARIs significantly activated hypothalamic neurons (KARI 101\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.029, KARI 201\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0152), resulting in increased food intake and improved gastric emptying and colonic transit in POI mice. In aged mice, KARIs markedly elevated plasma GH levels and restored gastrocnemius muscle mass (KARI 101\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0018, KARI 201\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0006) and improved rota\u2010rod performance (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) by downregulating expression of atrophic genes and upregulating myogenic genes. In cancer cachexia mice, KARIs improved food intake and preserved skeletal muscle mass at lower doses (gastrocnemius, 10\u2009mg\/kg;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) than synthetic GHSR \u2010 1a agonist (anamorelin, 30\u2009mg\/kg) and enhanced functional recovery (rota\u2010rod test, 10\u2009mg\/kg; KARI 101\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.045, KARI 201\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003) without affecting tumour growth.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>KARIs are potent, brain\u2010penetrant GHSR\u20101a agonists with favourable pharmacokinetics compared to anamorelin. They enhance appetite, preserve skeletal muscle mass and improve physical performance in models of aging and cancer cachexia, supporting their potential as next\u2010generation therapies for anorexia and muscle wasting.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70277","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T03:58:52Z","timestamp":1775102332000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["KARIs, Ghrelin Receptor Agonists With Excellent Brain Permeability, Increase Food Intake and Attenuate the Muscle Loss in Mice"],"prefix":"10.1002","volume":"17","author":[{"given":"Hee\u00a0Ji","family":"Yoon","sequence":"first","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan\u00a0Hui","family":"Han","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u00a0Bo","family":"Kim","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won\u00a0Gyeong","family":"Lee","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seo\u00a0Young","family":"Choi","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung\u00a0Jo","family":"Choi","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyeong","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Dankook University  Cheonan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Koo","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy Dankook University  Cheonan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihoon","family":"Lee","sequence":"additional","affiliation":[{"name":"BK21 FOUR Community\u2010Based Intelligent Novel Drug Discovery Education Unit, Vessel\u2010Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Im\u2010Sook","family":"Song","sequence":"additional","affiliation":[{"name":"BK21 FOUR Community\u2010Based Intelligent Novel Drug Discovery Education Unit, Vessel\u2010Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u00a0Hee","family":"Park","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee\u00a0Kyung","family":"Jin","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Laboratory Animal Medicine, College of Veterinary Medicine Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8270-0072","authenticated-orcid":false,"given":"Jae\u2010sung","family":"Bae","sequence":"additional","affiliation":[{"name":"KNU AD Research Institute Kyungpook National University  Daegu Republic of Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, School of Medicine Kyungpook National University  Daegu Republic of 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