{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:53:53Z","timestamp":1786985633060,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["MOST 109-2314-B-037-039"],"award-info":[{"award-number":["MOST 109-2314-B-037-039"]}]},{"name":"National Science and Technology Council, Taiwan","award":["MOST 110-2314-B-037-115"],"award-info":[{"award-number":["MOST 110-2314-B-037-115"]}]},{"name":"Kaohsiung Medical University Hospital, Taiwan","award":["KMUH109-9R50"],"award-info":[{"award-number":["KMUH109-9R50"]}]},{"name":"Kaohsiung Medical University Hospital, Taiwan","award":["KMUH110-0R50"],"award-info":[{"award-number":["KMUH110-0R50"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is driven in part by the accumulation of reactive metabolites like glyoxal (GO), which induces retinal pigment epithelium (RPE) degeneration. Here, we demonstrate that GO triggers ferroptosis in human ARPE-19 cells, as characterized by iron-dependent lipid peroxidation, glutathione depletion, and reactive oxygen species (ROS) accumulation. This ferroptotic cell death is coupled with profound mitochondrial dysfunction, featuring network fragmentation and the downregulation of the key regulators MFN2, PGC-1\u03b1, and SIRT1. We identify hepatoma-derived growth factor (HDGF) as a potent protector against GO-induced damage. HDGF operates through a dual mechanism: it activates the p38 MAPK\/AKT and SIRT1\/PGC-1\u03b1 axes to restore mitochondrial biogenesis and homeostasis, while concurrently enhancing the glutathione\/GPX4 antioxidant system to suppress ferroptosis. This cytoprotective action is mediated via the PGC-1\u03b1\/Nrf2 pathway, which integrates the enhancement of antioxidant defenses with the preservation of mitochondrial integrity. Our findings establish HDGF as a novel therapeutic agent for AMD, uniquely capable of concurrently targeting the interconnected pathways of ferroptosis and mitochondrial dysfunction, thereby addressing a critical unmet need in retinal disease treatment.<\/jats:p>","DOI":"10.3390\/antiox14121434","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T09:34:37Z","timestamp":1764581677000},"page":"1434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HDGF Protects Retinal Pigment Epithelium from Glyoxal-Induced Ferroptosis via SIRT1\/PGC-1\u03b1\/Nrf2 Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7208-4613","authenticated-orcid":false,"given":"Heng-Dao","family":"Lin","sequence":"first","affiliation":[{"name":"Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8760-5739","authenticated-orcid":false,"given":"Rong-Kung","family":"Tsai","sequence":"additional","affiliation":[{"name":"Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97403, Taiwan"},{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 97403, Taiwan"},{"name":"Doctoral Degree Program in Translational Medicine, Tzu Chi University and Academia Sinica, Hualien 97403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3359-8144","authenticated-orcid":false,"given":"Yao-Tseng","family":"Wen","sequence":"additional","affiliation":[{"name":"Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6417-4363","authenticated-orcid":false,"given":"Pei-Kang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807377, Taiwan"},{"name":"School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"\u015apiewak, D., Drzyzga, \u0141., Dorecka, M., and Wygl\u0119dowska-Promie\u0144ska, D. 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