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A hallmark of AMD is the presence of drusen, extracellular deposits rich in lipids, proteins, and cellular debris, which are secreted by the RPE. These deposits impair RPE function, promote chronic inflammation, and accelerate disease progression. Despite advancements in understanding AMD pathogenesis, therapeutic strategies targeting lipid dysregulation and oxidative damage in RPE cells remain limited. This study evaluated the effects of liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), on free fatty acid (FFA)-induced damage in ARPE-19 cells, a widely used in vitro model of RPE dysfunction. FFA treatment induced lipid droplet accumulation, oxidative stress, and epithelial\u2013mesenchymal transition (EMT), which are processes implicated in AMD progression. Liraglutide significantly reduced lipid droplet accumulation, mitigated oxidative stress, and suppressed EMT, as demonstrated by high-content imaging, immunocytochemistry, and molecular assays. Mechanistic analyses revealed that liraglutide activates AMP-activated protein kinase (AMPK), enhancing lipophagy and restoring lipid homeostasis. Furthermore, liraglutide influenced exosome secretion, altering paracrine signaling and reducing EMT markers in neighboring cells. These findings underscore liraglutide\u2019s potential to address critical mechanisms underlying AMD pathogenesis, including lipid dysregulation, oxidative stress, and EMT. This study provides foundational evidence supporting the development of GLP-1 receptor agonists as targeted therapies for AMD.<\/jats:p>","DOI":"10.3390\/ijms26083704","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T03:59:06Z","timestamp":1744689546000},"page":"3704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Liraglutide Attenuates FFA-Induced Retinal Pigment Epithelium Dysfunction via AMPK Activation and Lipid Homeostasis Regulation in ARPE-19 Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-028X","authenticated-orcid":false,"given":"Sing-Hua","family":"Tsou","sequence":"first","affiliation":[{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Shin","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"},{"name":"School of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"},{"name":"Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Ning","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"},{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-5467","authenticated-orcid":false,"given":"Edy","family":"Kornelius","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"},{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Ting","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0180-1822","authenticated-orcid":false,"given":"Hui-Chih","family":"Hung","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"},{"name":"Department of Life Sciences, Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-3652","authenticated-orcid":false,"given":"Yu-Chien","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4553-3727","authenticated-orcid":false,"given":"Chih-Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"},{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5488-4257","authenticated-orcid":false,"given":"Min-Yen","family":"Hsu","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan"},{"name":"Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, J., Lee, Y.J., and Won, J.Y. 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