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This review summarizes the expression, distribution, structure, processing, and secretion of GDF15. We also discuss multilayered regulatory networks governing GDF15 expression, including ATF4\/CHOP, AMPK, EGR1, EZH2, PPAR\u03b3, NRF2, ERR\u03b3, and p53, as well as posttranscriptional regulator CNOT6L. The GFRAL receptor is central to its function, mediating the anorexigenic and metabolic effects of GDF15. This review synthesizes evidence linking GDF15 to obesity, diabetes, cardiovascular diseases, metabolic liver disorders, cachexia, sarcopenia, and aging while exploring its interactions with key metabolic factors including FGF21, GLP-1, leptin, and glucocorticoids. Lifestyle interventions such as ketogenic, high-fat diets, and exercise modulate GDF15 levels, underscoring its role in pan-metabolic health. Pharmacologically, various agents\u2014including anti-hyperglycemic agents and natural compounds\u2014induce GDF15 expression, implicating their therapeutic potential in cardiometabolic diseases. We comprehensively evaluate current advances in GDF15-targeted drug development, including monoclonal antibodies, fusion proteins, and small-molecule drugs, to provide a scientific foundation for innovative therapies. Finally, we outline unresolved issues in GDF15 biology and therapeutics, such as the exploration of peripheral receptors, contradictory findings in studies of cardiometabolic diseases, and the persistent challenges in developing GDF15-targeted therapeutics.<\/jats:p>","DOI":"10.34133\/research.0832","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T11:33:37Z","timestamp":1753097617000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":32,"title":["Emerging Roles of GDF15 in Metabolic and Cardiovascular Diseases"],"prefix":"10.34133","volume":"8","author":[{"given":"Tian","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, \rUniversity of Science and Technology of China, Hefei 230001, China."},{"name":"Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, \rUniversity of Science and Technology of China, Hefei 230001, China."},{"name":"Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Little","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, \rThe University of Queensland, Woolloongabba, QLD4102, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Strijdom","sequence":"additional","affiliation":[{"name":"Centre for Cardio-metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, \rStellenbosch University, Cape Town, South Africa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, \rUniversity of Science and Technology of China, Hefei 230001, China."},{"name":"Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5488-5217","authenticated-orcid":true,"given":"Suowen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, \rUniversity of Science and Technology of China, Hefei 230001, China."},{"name":"Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"issue":"1","key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jlb.65.1.2","article-title":"MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation","volume":"65","author":"Fairlie WD","year":"1999","unstructured":"Fairlie WD, Moore AG, Bauskin AR, Russell PK, Zhang HP, Breit SN. 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