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New treatments are required for fibrosis, autophagy, and microglia-driven pathologies in AMD patients for personalized medicine approaches, considering that only 10% of AMD patients are treated using the current medicine. The current study examined ninety-one compounds using a phenotypic drug discovery platform in vitro and in vivo to find potential drug candidates that include a new chemical entity (NCE) and extracts from plants such as Diospyros kaki, Achyranthes japonica, and Glycyrrhiza uralensis. The phenotypic drug discovery platform determined mitochondrial function quantitatively by measuring the oxygen consumption rate (OCR) and reactive oxygen species (ROS) of drug-treated cells under oxidative stress in addition to the neuroprotective efficacy test of each candidate. In vitro screening using ARPE-19 cells under oxidative stress identified 18 compounds with significant cytoprotective effects. Among these, JK-14, JK-18, JK-52, and JK-65 demonstrated dose-dependent restoration of cell viability and mitochondrial function, showing a recovered oxygen consumption rate, including basal respiration, ATP-linked respiration, and maximal respiration. In vivo studies used a zebrafish (Danio rerio) model of dry AMD induced by intense blue light exposure. Treatment with natural product candidates, including JK-502, JK-504, JK-505, JK-508, JK-509, JK-514, and JK-520, significantly increased the outer nuclear layer (ONL) thickness, showing a 37% increase compared to blue light-exposed controls, and improved inner retinal layer integrity, including the inner nuclear layer (INL) and inner plexiform layer (IPL). Moreover, the recovery of ganglion cell layer (GCL) nuclei counts further supported the neuroprotective efficacy of these treatments. The current data demonstrate that synthetic small-molecule and natural-product-based formulations can effectively mitigate oxidative stress-induced retinal degeneration. These promising neuroprotectants warrant further investigation as potential therapeutic agents for AMD.<\/jats:p>","DOI":"10.1021\/acsomega.5c02227","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T19:44:32Z","timestamp":1751917472000},"page":"30467-30488","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Drug\nDiscovery Platform by Quantitative\nHigh-Throughput Screening Identifies Antiapoptotic Molecules in a\nZebrafish Model of Age-Related Macular Degeneration"],"prefix":"10.1021","volume":"10","author":[{"given":"Kyung\nHae","family":"Lee","sequence":"first","affiliation":[{"name":"Julia Laboratory , , ,","place":["Suwon, Korea, 16232"]},{"name":"Julia Eye Institute , , ,","place":["Suwon, Korea, 16243"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8891-7582","authenticated-orcid":true,"given":"Bongkyun","family":"Park","sequence":"additional","affiliation":[{"name":"Korea 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32943"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeeun","family":"Jung","sequence":"additional","affiliation":[{"name":"Gyeongsangnam-do Agricultural Research and Extension Services , , ,","place":["Gimhae, Korea, 52733"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwang-Hwan","family":"Ahn","sequence":"additional","affiliation":[{"name":"Gyeongsangnam-do Agricultural Research and Extension Services , , ,","place":["Gimhae, Korea, 52733"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Sook","family":"Kim","sequence":"additional","affiliation":[{"name":"Julia Laboratory , , ,","place":["Suwon, Korea, 16232"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Won","family":"Choo","sequence":"additional","affiliation":[{"name":"Bio Campus of Korea Polytechnic University , , ,","place":["Nonsan, Korea, 32943"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay M.","family":"Stewart","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Hyun","family":"Jee","sequence":"additional","affiliation":[{"name":"The Catholic University of Korea , , ,","place":["Suwon, Korea, 16247"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-7739","authenticated-orcid":true,"given":"Wan Jin","family":"Jahng","sequence":"additional","affiliation":[{"name":"Julia Laboratory , , ,","place":["Suwon, Korea, 16232"]},{"name":"Julia Eye Institute , , ,","place":["Suwon, Korea, 16243"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"issue":"7","key":"2026081812232697100_cit1","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1021\/cr960141c","article-title":"The 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