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Resveratrol is a natural polyphenol with well-established antioxidant and anti-apoptotic properties. This study investigated whether resveratrol exerts cytoprotective effects when combined with anti-VEGFs on ARPE-19 cells in vitro. Cells were treated with ranibizumab (RNZ), aflibercept (AFL), or ziv-aflibercept (ZFL), either alone or in combination with resveratrol. Mitochondrial and cytosolic reactive oxygen species (MitROS and CytROS), mitochondrial membrane depolarization (MitDep), caspase-3, -8 and -9 activities, cell viability, apoptosis, and VEGF-A levels were evaluated using confocal microscopy, plate reader-based assays, and ELISA techniques. Anti-VEGFs induced tolerable oxidative or apoptotic stress in ARPE-19 cells but did not exhibit intrinsic antioxidant and cytoprotective effects. The addition of resveratrol significantly enhanced beneficial effects by reducing oxidative stress, preserving mitochondrial integrity, and suppressing intrinsic apoptotic signalling, while increasing cell viability. VEGF-A levels were effectively reduced by anti-VEGF treatment, and this suppression was further augmented by resveratrol without compromising cellular survival. These findings indicate that resveratrol acts as an additive modulator that strengthens the cellular effects of anti-VEGFs on ARPE-19 cells. The combination strategy may represent a supportive approach to optimize long-term anti-VEGF therapy in AMD.<\/jats:p>","DOI":"10.3390\/biom16060883","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"883","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An In Vitro Evaluation of a New Approach in AMD: Effects of the Combination of Resveratrol and Anti-VEGFs on ARPE-19 Cells"],"prefix":"10.3390","volume":"16","author":[{"given":"Onur","family":"Konukcu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, S\u00fcleyman Demirel University Research and Education Hospital, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6877-4884","authenticated-orcid":false,"given":"Mehmet","family":"Argun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, S\u00fcleyman Demirel University Research and Education Hospital, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4956-3774","authenticated-orcid":false,"given":"Semra","family":"Acer","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, S\u00fcleyman Demirel University Research and Education Hospital, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9262-996X","authenticated-orcid":false,"given":"\u00d6mer","family":"\u00c7elik","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medical, Suleyman Demirel University, Isparta TR-32260, T\u00fcrkiye"},{"name":"Neuroscience Research Center, Suleyman Demirel University, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zlem","family":"T\u00f6k","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, S\u00fcleyman Demirel University Research and Education Hospital, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levent","family":"T\u00f6k","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, S\u00fcleyman Demirel University Research and Education Hospital, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0887-6974","authenticated-orcid":false,"given":"Mustafa","family":"Naz\u0131ro\u011flu","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medical, Suleyman Demirel University, Isparta TR-32260, T\u00fcrkiye"},{"name":"Neuroscience Research Center, Suleyman Demirel University, Isparta TR-32260, T\u00fcrkiye"},{"name":"Drug Discovery Unit, BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture and Industry Ltd., G\u00f6ller B\u00f6lgesi Teknokenti, Isparta TR-32260, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1159\/000517520","article-title":"Age-Related Macular Degeneration: Pathophysiology, Management, and Future Perspectives","volume":"244","author":"Flores","year":"2021","journal-title":"Ophthalmologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global Prevalence of Age-Related Macular Degeneration and Disease Burden Projection for 2020 and 2040: A Systematic Review and Meta-Analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. 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