{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T04:17:47Z","timestamp":1785039467090,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["LTGY24H030011"],"award-info":[{"award-number":["LTGY24H030011"]}]},{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["Y2020228"],"award-info":[{"award-number":["Y2020228"]}]},{"name":"Wenzhou Public Welfare Science and Technology Project","award":["LTGY24H030011"],"award-info":[{"award-number":["LTGY24H030011"]}]},{"name":"Wenzhou Public Welfare Science and Technology Project","award":["Y2020228"],"award-info":[{"award-number":["Y2020228"]}]},{"name":"The Summit Advancement Disciplines of Zhejiang Province (Wenzhou Medical University\u2014Pharmaceutics)","award":["LTGY24H030011"],"award-info":[{"award-number":["LTGY24H030011"]}]},{"name":"The Summit Advancement Disciplines of Zhejiang Province (Wenzhou Medical University\u2014Pharmaceutics)","award":["Y2020228"],"award-info":[{"award-number":["Y2020228"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21D2D3. This was achieved by substituting the R96\u2013V106 region of FGF21 (the binding site with the D2\u2013D3 domain of FGFR1c) with the corresponding region from FGF1. Structural characterization and binding affinity tests showed that the analog\u2019s capacity to bind FGFR1c was significantly enhanced compared to wild-type FGF21 (FGF21WT). In a T2D mouse model, we found that FGF21D2D3 had greater potency than FGF21WT in improving hyperlipidemia and DCM. Furthermore, mechanistic studies revealed that FGF21D2D3 more effectively bound FGFR1, activated AMPK, inhibited oxidative stress, and ameliorated DCM. Therefore, our data indicate that FGF21D2D3 is a better substitute for FGF21WT in treating DCM by improving dyslipidemia and directly suppressing oxidative stress via FGFR1\u2013AMPK activation in T2D.<\/jats:p>","DOI":"10.3390\/ijms26146577","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T12:46:33Z","timestamp":1752237993000},"page":"6577","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Development of FGF21 Mutant with Potent Cardioprotective Effects in T2D Mice via FGFR1\u2013AMPK-Mediated Inhibition of Oxidative Stress"],"prefix":"10.3390","volume":"26","author":[{"given":"Ziying","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruina","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxia","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0214-971X","authenticated-orcid":false,"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1161\/CIRCRESAHA.120.315913","article-title":"Basic Mechanisms of Diabetic Heart Disease","volume":"126","author":"Ritchie","year":"2020","journal-title":"Circ. 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