{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T17:18:32Z","timestamp":1786295912434,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471093"],"award-info":[{"award-number":["82471093"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171064"],"award-info":[{"award-number":["82171064"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022A1515012514"],"award-info":[{"award-number":["2022A1515012514"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["JCYJ20230807091503007"],"award-info":[{"award-number":["JCYJ20230807091503007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["82471093"],"award-info":[{"award-number":["82471093"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["82171064"],"award-info":[{"award-number":["82171064"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2022A1515012514"],"award-info":[{"award-number":["2022A1515012514"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["JCYJ20230807091503007"],"award-info":[{"award-number":["JCYJ20230807091503007"]}]},{"name":"Shenzhen Science and Technology Program","award":["82471093"],"award-info":[{"award-number":["82471093"]}]},{"name":"Shenzhen Science and Technology Program","award":["82171064"],"award-info":[{"award-number":["82171064"]}]},{"name":"Shenzhen Science and Technology Program","award":["2022A1515012514"],"award-info":[{"award-number":["2022A1515012514"]}]},{"name":"Shenzhen Science and Technology Program","award":["JCYJ20230807091503007"],"award-info":[{"award-number":["JCYJ20230807091503007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is a common disease contributing to vision loss in the elderly. All-trans-retinal (atRAL) is a retinoid in the retina, and its abnormal accumulation exhibits toxicity to the retina and promotes oxidative stress-induced photoreceptor degeneration, which plays a crucial role in AMD progression. Crocin is a natural product extracted from saffron, which displays significant antioxidant and anti-inflammatory effects. The present study elucidates the protective effects of crocin on photoreceptor cell damage by atRAL and its potential mechanisms. The results revealed that crocin significantly attenuated cytotoxicity by repressing oxidative stress, mitochondrial injury, and DNA damage in atRAL-loaded photoreceptor cells. Moreover, crocin visibly inhibited DNA damage-induced apoptosis and gasdermin E (GSDME)-mediated pyroptosis in photoreceptor cells after exposure to atRAL. It was also observed that crocin distinctly prevented an increase in Fe2+ levels and lipid peroxidation caused by atRAL via suppressing the Kelch-like ECH-associated protein 1 (KEAP1)\/nuclear factor-erythroid 2-related factor 2 (NRF2)\/heme oxygenase-1 (HO-1) signaling pathway, thereby ameliorating photoreceptor cell ferroptosis. In short, these findings provide new insights that crocin mitigates atRAL-induced toxicity to photoreceptor cells by inhibiting oxidative stress, apoptosis, pyroptosis, and ferroptosis.<\/jats:p>","DOI":"10.3390\/ijms251810124","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T10:49:48Z","timestamp":1726829388000},"page":"10124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Crocin Protects the 661W Murine Photoreceptor Cell Line against the Toxic Effects of All-Trans-Retinal"],"prefix":"10.3390","volume":"25","author":[{"given":"Bo","family":"Yang","sequence":"first","affiliation":[{"name":"Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4199-1685","authenticated-orcid":false,"given":"Kunhuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingmeng","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"Shenzhen Research Institute of Xiamen University, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5906-5675","authenticated-orcid":false,"given":"Yalin","family":"Wu","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"Shenzhen Research Institute of Xiamen University, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41572-021-00265-2","article-title":"Age-related macular degeneration","volume":"7","author":"Fleckenstein","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1001\/jama.2023.26074","article-title":"Age-Related Macular Degeneration: A Review","volume":"331","author":"Fleckenstein","year":"2024","journal-title":"JAMA"},{"key":"ref_4","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. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1167\/iovs.15-18429","article-title":"Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids","volume":"57","author":"Liu","year":"2016","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.1074\/jbc.M111.315432","article-title":"Mechanism of all-trans-retinal toxicity with implications for stargardt disease and age-related macular degeneration","volume":"287","author":"Chen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6958","DOI":"10.1074\/jbc.RA120.013189","article-title":"Activation of JNK signaling promotes all-trans-retinal-induced photoreceptor apoptosis in mice","volume":"295","author":"Liao","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"He, D., Tao, L., Cai, B., Chen, X., Wang, Y., Li, S., Liao, C., Chen, Y., Chen, J., and Liu, Z. (2023). eIF2alpha incites photoreceptor cell and retina damage by all-trans-retinal. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.104686"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cai, B., Liao, C., He, D., Chen, J., Han, J., Lu, J., Qin, K., Liang, W., Wu, X., and Liu, Z. (2022). Gasdermin E mediates photoreceptor damage by all-trans-retinal in the mouse retina. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2021.101553"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, C., Chen, J., Wang, Y., Liu, Z., and Wu, Y. (2021). Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance. J. Biol. Chem., 296.","DOI":"10.1074\/jbc.RA120.015779"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.freeradbiomed.2022.12.008","article-title":"Induction of ferroptosis by HO-1 contributes to retinal degeneration in mice with defective clearance of all-trans-retinal","volume":"194","author":"Chen","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10709","DOI":"10.1080\/10408398.2022.2084600","article-title":"Health benefits of astaxanthin against age-related diseases of multiple organs: A comprehensive review","volume":"63","author":"Alugoju","year":"2023","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111521","DOI":"10.1016\/j.fct.2020.111521","article-title":"Crocin: A fighter against inflammation and pain","volume":"143","author":"Hashemzaei","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111739","DOI":"10.1016\/j.fct.2020.111739","article-title":"Therapeutic potentials of crocin in medication of neurological disorders","volume":"145","author":"Ahmed","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.fct.2018.12.031","article-title":"Crocin attenuates methylglyoxal-induced osteoclast dysfunction by regulating glyoxalase, oxidative stress, and mitochondrial function","volume":"124","author":"Suh","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fernandez-Albarral, J.A., Ramirez, A.I., de Hoz, R., Lopez-Villarin, N., Salobrar-Garcia, E., Lopez-Cuenca, I., Licastro, E., Inarejos-Garcia, A.M., Almodovar, P., and Pinazo-Duran, M.D. (2019). Neuroprotective and Anti-Inflammatory Effects of a Hydrophilic Saffron Extract in a Model of Glaucoma. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174110"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.exer.2012.11.011","article-title":"Crocin prevents retinal ischaemia\/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K\/AKT signalling pathway","volume":"107","author":"Qi","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ajo.2018.03.007","article-title":"Effects of Crocin on Diabetic Maculopathy: A Placebo-Controlled Randomized Clinical Trial","volume":"190","author":"Sepahi","year":"2018","journal-title":"Am. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4579","DOI":"10.1016\/j.molcel.2021.09.003","article-title":"Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity","volume":"81","author":"Hou","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41575-023-00743-w","article-title":"The gasdermin protein family: Emerging roles in gastrointestinal health and disease","volume":"20","author":"Privitera","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41467-023-44669-y","article-title":"Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death","volume":"15","author":"Ma","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/j.molcel.2022.03.022","article-title":"Ferroptosis at the intersection of lipid metabolism and cellular signaling","volume":"82","author":"Liang","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eabl8920","DOI":"10.1126\/sciadv.abl8920","article-title":"Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion","volume":"8","author":"Maremonti","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.freeradbiomed.2020.06.023","article-title":"xCT regulates redox homeostasis and promotes photoreceptor survival after retinal detachment","volume":"158","author":"Gao","year":"2020","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhi, X., Lu, H., Ma, D., Liu, J., Luo, L., Wang, L., and Qin, Y. (2024). Melatonin protects photoreceptor cells against ferroptosis in dry AMD disorder by inhibiting GSK-3B\/Fyn-dependent Nrf2 nuclear translocation. Biochim. Biophys. Acta Mol. Basis Dis., 1870.","DOI":"10.1016\/j.bbadis.2023.166969"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9461","DOI":"10.1074\/jbc.RA119.008697","article-title":"The selective estrogen receptor modulator raloxifene mitigates the effect of all-trans-retinal toxicity in photoreceptor degeneration","volume":"294","author":"Getter","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1172\/JCI80950","article-title":"Molecular pharmacodynamics of emixustat in protection against retinal degeneration","volume":"125","author":"Zhang","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4917","DOI":"10.1167\/iovs.09-3581","article-title":"Evaluation of potential therapies for a mouse model of human age-related macular degeneration caused by delayed all-trans-retinal clearance","volume":"50","author":"Maeda","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1146\/annurev.pharmtox.47.120505.105225","article-title":"Diseases caused by defects in the visual cycle: Retinoids as potential therapeutic agents","volume":"47","author":"Travis","year":"2007","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1167\/iovs.15-18551","article-title":"Interphotoreceptor Retinoid-Binding Protein Mitigates Cellular Oxidative Stress and Mitochondrial Dysfunction Induced by All-trans-Retinal","volume":"57","author":"Lee","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1111\/bph.14650","article-title":"Simvastatin protects photoreceptors from oxidative stress induced by all-trans-retinal, through the up-regulation of interphotoreceptor retinoid binding protein","volume":"176","author":"Zhang","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3859","DOI":"10.1002\/ptr.7583","article-title":"Crocin molecular signaling pathways at a glance: A comprehensive review","volume":"36","author":"Boozari","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3232","DOI":"10.1080\/10408398.2020.1864279","article-title":"Saffron bioactives crocin, crocetin and safranal: Effect on oxidative stress and mechanisms of action","volume":"62","author":"Pastor","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109297","DOI":"10.1016\/j.intimp.2022.109297","article-title":"Hepatoprotective effects of carvedilol and crocin against leflunomide-induced liver injury","volume":"113","author":"Sokar","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jare.2022.02.015","article-title":"A natural carotenoid crocin exerts antidepressant action by promoting adult hippocampal neurogenesis through Wnt\/\u03b2-catenin signaling","volume":"43","author":"Tao","year":"2023","journal-title":"J. Adv. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120628","DOI":"10.1016\/j.carbpol.2023.120628","article-title":"ROS-sensitive Crocin-loaded chitosan microspheres for lung targeting and attenuation of radiation-induced lung injury","volume":"307","author":"Wang","year":"2023","journal-title":"Carbohydr. Polym."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1167\/iovs.05-1621","article-title":"Protective effect of crocin against blue light- and white light-mediated photoreceptor cell death in bovine and primate retinal primary cell culture","volume":"47","author":"Laabich","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.cell.2023.11.044","article-title":"Cell death","volume":"187","author":"Newton","year":"2024","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41580-018-0089-8","article-title":"Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins","volume":"20","author":"Singh","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41581-023-00694-0","article-title":"Regulated cell death pathways in kidney disease","volume":"19","author":"Sanz","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41580-023-00689-6","article-title":"A guide to cell death pathways","volume":"25","author":"Yuan","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41581-022-00662-0","article-title":"Gasdermins and pyroptosis in the kidney","volume":"19","author":"Elias","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41392-021-00507-5","article-title":"Pyroptosis: Mechanisms and diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41577-019-0228-2","article-title":"The gasdermins, a protein family executing cell death and inflammation","volume":"20","author":"Broz","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.tcb.2017.05.005","article-title":"Gasdermins: Effectors of Pyroptosis","volume":"27","author":"Kovacs","year":"2017","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","article-title":"Ferroptosis: Molecular mechanisms and health implications","volume":"31","author":"Tang","year":"2021","journal-title":"Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1073\/pnas.1821022116","article-title":"Ferroptosis as a target for protection against cardiomyopathy","volume":"116","author":"Fang","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Tang, Z., Ju, Y., Dai, X., Ni, N., Liu, Y., Zhang, D., Gao, H., Sun, H., Zhang, J., and Gu, P. (2021). HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration. Redox Biol., 43.","DOI":"10.1016\/j.redox.2021.101971"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10124\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:01:07Z","timestamp":1760112067000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,20]]},"references-count":49,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms251810124"],"URL":"https:\/\/doi.org\/10.3390\/ijms251810124","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,20]]}}}