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It is expressed in various tissues and its circulating levels rise during exercise, aging, pregnancy, and conditions such as cancer, cardiovascular disease, and infections. The biological activities of GDF15, including anorexia and cachexia, are primarily mediated through the GFRAL receptor, localized in the brainstem and functioning via RET co\u2010receptor recruitment. This signaling is crucial for energy homeostasis and nausea induction. Recent studies suggest a broader GFRAL distribution, potentially explaining GDF15\u2032s distinct roles. These findings sparked interest in leveraging GDF15\u2010GFRAL pathways for therapeutic development. Two primary strategies include GDF15 analogues as GFRAL agonists for obesity treatment and GDF15\u2010derived peptides as antagonists to counteract cancer\u2010induced cachexia and related disorders. This review highlights advancements in understanding GDF15\u2010GFRAL signaling and its implications, summarizing bioactive GDF15\u2010derived molecules, their pharmacological applications, and offering insights into novel treatment avenues for GDF15\u2010associated conditions.<\/jats:p>","DOI":"10.1002\/cmdc.202400961","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:24:11Z","timestamp":1738740251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["GDF15 Analogues Acting as GFRAL Ligands"],"prefix":"10.1002","volume":"20","author":[{"given":"Andrea","family":"Di Santo","sequence":"first","affiliation":[{"name":"Department of Neuroscience Psychology Pharmacology and Infant Health Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology University of  Florence Via Ugo Schiff, 6, Sesto Fiorentino FI, 50019 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Tarchi","sequence":"additional","affiliation":[{"name":"Department of Health Science Psychiatry Unit University of Florence, Largo Brambilla 3  Florence FI, 50134 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Villa","sequence":"additional","affiliation":[{"name":"Department of Health Science Anesthesiology Unit University of Florence, Largo Brambilla 3  Florence FI, 50134 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Castellini","sequence":"additional","affiliation":[{"name":"Department of Health Science Psychiatry Unit University of Florence, Largo Brambilla 3  Florence FI, 50134 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valdo","family":"Ricca","sequence":"additional","affiliation":[{"name":"Department of Health Science Psychiatry Unit University of Florence, Largo Brambilla 3  Florence FI, 50134 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Squecco","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine Section of Physiological Sciences University of Florence, Viale Morgagni 63  Florence FI, 50134 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Papini","sequence":"additional","affiliation":[{"name":"Department of Chemistry \u201cUgo Schiff\u201d Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology University of  Florence via della Lastruccia, 3\u201313, Sesto Fiorentino FI, 50019 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feliciana","family":"Real\u2010Fernandez","sequence":"additional","affiliation":[{"name":"Institute of Chemistry of Organometallic Compounds \u2013 National, Research Council of Italy (ICCOM-CNR)  Via Madonna del Piano, 10, Sesto Fiorentino FI, 50019 Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9577-5228","authenticated-orcid":false,"given":"Paolo","family":"Rovero","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Psychology Pharmacology and Infant Health Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology University of  Florence Via Ugo Schiff, 6, Sesto Fiorentino FI, 50019 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,17]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(97)00485-X"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.21.11514"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2013.05.003"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.12.016"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2010.00629.x"},{"key":"e_1_2_7_6_1","first-page":"4781","volume":"85","author":"Moore A. 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