{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:42:42Z","timestamp":1785404562252,"version":"3.56.0"},"reference-count":105,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004478","name":"Beijing Union University","doi-asserted-by":"publisher","award":["ZK10202501"],"award-info":[{"award-number":["ZK10202501"]}],"id":[{"id":"10.13039\/501100004478","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ZK10202501"],"award-info":[{"award-number":["ZK10202501"]}],"id":[{"id":"https:\/\/ror.org\/01hg31662","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017662","name":"State Administration for Market Regulation","doi-asserted-by":"publisher","award":["SSZX-2024-BJ-03"],"award-info":[{"award-number":["SSZX-2024-BJ-03"]}],"id":[{"id":"10.13039\/100017662","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SSZX-2024-BJ-03"],"award-info":[{"award-number":["SSZX-2024-BJ-03"]}],"id":[{"id":"https:\/\/ror.org\/00aaqtw69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Oxidative stress contributes to retinal neurovascular injury through inflammation, mitochondrial dysfunction, blood\u2013retinal barrier (BRB) disruption, microcirculatory impairment, and regulated cell death. Hydroxysafflor yellow A (HSYA), a water-soluble quinochalcone C-glycoside derived from safflower (Carthamus tinctorius L.), modulates oxidative and inflammatory signaling, apoptosis, mitochondrial injury, endothelial barrier dysfunction, and neurovascular damage in experimental ischemic, inflammatory, and metabolic disorders. This review critically evaluates the direct ocular evidence for HSYA in diabetic retinopathy and examines the systemic-to-ocular pharmacokinetic and delivery barriers that constrain its ophthalmic translation. Current ocular evidence is limited and concentrated mainly in DR models, in which HSYA attenuates oxidative stress, inflammation, BRB disruption, and apoptosis, potentially through Nrf2\/HO-1 signaling. Evidence in retinal photic injury is limited, whereas the proposed relevance of HSYA to retinal ischemia\u2013reperfusion injury, glaucoma, and AMD remains largely hypothesis-generating. The principal translational challenge is whether HSYA can achieve pharmacologically relevant exposure in ocular target tissues. Future studies should integrate dose, plasma and ocular exposure, target engagement, retinal structure, local safety, and visual function in disease-specific models. Accordingly, evidence from non-DR models is discussed primarily to define mechanistic hypotheses and experimental priorities rather than to establish ophthalmic efficacy.<\/jats:p>","DOI":"10.3390\/antiox15070865","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:16:28Z","timestamp":1783689388000},"page":"865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydroxysafflor Yellow A for Diabetic Retinopathy: A Critical Review of Retinal Neurovascular Mechanisms and Systemic-to-Ocular Pharmacokinetic Barriers"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0456-5060","authenticated-orcid":false,"given":"Jiaqi","family":"Liu","sequence":"first","affiliation":[{"name":"College of Biochemical Engineering, Beijing Union University, Beijing 100023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Biochemical Engineering, Beijing Union University, Beijing 100023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Li","sequence":"additional","affiliation":[{"name":"College of Biochemical Engineering, Beijing Union University, Beijing 100023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Biochemical Engineering, Beijing Union University, Beijing 100023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Biochemical Engineering, Beijing Union University, Beijing 100023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Biochemical Engineering, Beijing Union University, Beijing 100023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","first-page":"2803","article-title":"The impact of aging on ocular diseases: Unveiling complex interactions","volume":"16","author":"You","year":"2024","journal-title":"Aging Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102407","DOI":"10.1016\/j.arr.2024.102407","article-title":"Aging of the eye: Lessons from cataracts and age-related macular degeneration","volume":"99","author":"Cvekl","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"546","DOI":"10.14336\/AD.2023.0630-1","article-title":"Aging, cellular senescence, and glaucoma","volume":"15","author":"Zhang","year":"2024","journal-title":"Aging Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wici\u0144ski, M., Fajkiel-Madajczyk, A., Kurant, Z., Rzepi\u0144ski, \u0141., and S\u0142upski, M. (2026). Review of Therapeutic Potential of Coenzyme Q10 in Ophthalmology: Focus on Age-Related Macular Degeneration, Glaucoma, and Retinitis Pigmentosa. Antioxidants, 15.","DOI":"10.3390\/antiox15040506"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41392-025-02253-4","article-title":"Mitochondria in oxidative stress, inflammation and aging: From mechanisms to therapeutic advances","volume":"10","author":"Xu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"136","DOI":"10.51329\/mehdiophthal1527","article-title":"Reactive oxygen species and oxidative stress in ocular disease: From molecular mechanisms to targeted therapies","volume":"14","author":"Abukhaled","year":"2025","journal-title":"Med. Hypothesis Discov. Innov. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yan, Y., Wu, Y., Zhao, Y., Yang, Y., An, G., Liu, Z., and Qi, D. (2025). A review on eye diseases induced by blue light: Pathology, model, active ingredients and mechanisms. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1513406"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.survophthal.2024.07.004","article-title":"Retinal light damage: From mechanisms to protective strategies","volume":"69","author":"Zhang","year":"2024","journal-title":"Surv. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"043603","DOI":"10.1155\/2007\/43603","article-title":"Oxidative stress and diabetic retinopathy","volume":"2007","author":"Kowluru","year":"2007","journal-title":"J. Diabetes Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Albarral, J.A., Ram\u00edrez, A.I., de Hoz, R., Matamoros, J.A., Salobrar-Garc\u00eda, E., Elvira-Hurtado, L., L\u00f3pez-Cuenca, I., S\u00e1nchez-Puebla, L., Salazar, J.J., and Ram\u00edrez, J.M. (2024). Glaucoma: From pathogenic mechanisms to retinal glial cell response to damage. Front. Cell. Neurosci., 18.","DOI":"10.3389\/fncel.2024.1354569"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Reddy, S.K., Devi, V., Seetharaman, A.T., Shailaja, S., Bhat, K.M., Gangaraju, R., and Upadhya, D. (2024). Cell and molecular targeted therapies for diabetic retinopathy. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1416668"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Medina-Arellano, A.E., Albert-Garay, J.S., Medina-S\u00e1nchez, T., Fonseca, K.H., Ruiz-Cruz, M., and Ochoa-de la Paz, L. (2024). M\u00fcller cells and retinal angiogenesis: Critical regulators in health and disease. Front. Cell. Neurosci., 18.","DOI":"10.3389\/fncel.2024.1513686"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shen, W. (2025). Retinal neurovascular coupling: From mechanisms to a diagnostic window into brain disorders. Cells, 14.","DOI":"10.3390\/cells14221798"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3892\/ijmm.2025.5643","article-title":"Mechanisms of action of retinal microglia in diabetic retinopathy","volume":"56","author":"Bai","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, M., Yang, L., Zhai, H., Qiao, L., Wang, Z., An, X., and Wang, J. (2025). A new perspective on protecting the blood-retinal barrier against injury in diabetic retinopathy: Mitophagy. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1617797"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, Y., An, J., Zhou, J., Chang, L., Zhang, Q., and Peng, F. (2025). Hydroxysafflor yellow A: A natural pigment with potential anticancer therapeutic effect. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1495393"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mao, T., Jiang, K., Pang, Y., Pan, Y., Jia, W., Gao, Q., and Lin, Q. (2025). Hydroxysafflor yellow A for ischemic heart diseases: A systematic review and meta-analysis of animal experiments. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1510657"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, Q., Yang, Z., Guo, L., Li, Z., Liu, Y., Feng, S., and Wang, Y. (2023). Chemical composition, pharmacology and pharmacokinetic studies of GuHong injection in the treatment of ischemic stroke. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1261326"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bacchetti, T., Morresi, C., Bellachioma, L., and Ferretti, G. (2020). Antioxidant and pro-oxidant properties of Carthamus tinctorius, hydroxy safflor yellow A, and safflor yellow A. Antioxidants, 9.","DOI":"10.3390\/antiox9020119"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110576","DOI":"10.1016\/j.neuropharm.2025.110576","article-title":"Hydroxysafflor yellow A attenuates the blood-brain barrier dysfunction and neuroinflammation through anti-inflammatory microglial polarization after intracerebral hemorrhage","volume":"278","author":"Zheng","year":"2025","journal-title":"Neuropharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"104654","DOI":"10.1016\/j.phrs.2020.104654","article-title":"Pharmacological potential of the combination of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) for diabetes mellitus and its cardiovascular complications","volume":"153","author":"Orgah","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"113462","DOI":"10.1016\/j.biopha.2022.113462","article-title":"Comprehensive review of two groups of flavonoids in Carthamus tinctorius L","volume":"153","author":"Xian","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ren, F., Tan, Z., Hu, S., Rao, C., Xiang, Q., Wen, J., Chen, Y., and Peng, C. (2025). Pharmacological actions and applications of safflower flavonoids. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1637053"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bai, H., Yang, J., and Wang, R. (2025). Carthamus tinctorius L.: A comprehensive review of its ethnomedicine, phytochemistry, pharmacology, and clinical applications. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1609299"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4489","DOI":"10.1038\/s41467-025-59774-3","article-title":"Elucidation of the biosynthetic pathway of hydroxysafflor yellow A","volume":"16","author":"Wang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_26","first-page":"e004","article-title":"Current advances of Carthamus tinctorius L.: A review of its application and molecular regulation of flavonoid biosynthesis","volume":"3","author":"Wu","year":"2024","journal-title":"Med. Plant Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"153694","DOI":"10.1016\/j.phymed.2021.153694","article-title":"Hydroxysafflor yellow A, a natural compound from Carthamus tinctorius L with good effect of alleviating atherosclerosis","volume":"91","author":"Xue","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhu, H., Ni, X., Yu, Z., Liang, S., Qiu, Y., Huang, J., Tang, T., Wang, Y., Hu, E., and Li, T. (J. Pharm. Anal., 2025). Emerging natural product development strategies drive the therapeutic potential exploration and clinical translation of hydroxysafflor yellow A, J. Pharm. Anal., in press.","DOI":"10.1016\/j.jpha.2025.101534"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhao, F., Wang, P., Jiao, Y., Zhang, X., Chen, D., and Xu, H. (2020). Hydroxysafflor yellow A: A systematical review on botanical resources, physicochemical properties, drug delivery system, pharmacokinetics, and pharmacological effects. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.579332"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"129090","DOI":"10.1016\/j.foodchem.2021.129090","article-title":"Greener extraction process and enhanced in vivo bioavailability of bioactive components from Carthamus tinctorius L. by natural deep eutectic solvents","volume":"348","author":"Tong","year":"2021","journal-title":"Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1515\/biol-2022-0030","article-title":"Hydroxysafflor yellow A improved retinopathy via Nrf2\/HO-1 pathway in rats","volume":"17","author":"Sun","year":"2022","journal-title":"Open Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, Y., Liu, X., Zhang, P., Li, Y., Sun, M., Wang, Y., Wang, S., Yang, H., Liu, B., and Wang, M. (2022). Hydroxysafflor yellow A blocks HIF-1\u03b1 induction of NOX2 and protects ZO-1 protein in cerebral microvascular endothelium. Antioxidants, 11.","DOI":"10.21203\/rs.3.rs-1180303\/v1"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hudson, N., and Campbell, M. (2021). Tight junctions of the neurovascular unit. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.752781"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/cpdd.1487","article-title":"The Safety, Tolerability, and Pharmacokinetics of Active Ingredients From Hydroxysafflor Yellow A in Healthy Chinese Volunteers","volume":"14","author":"Zhao","year":"2025","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s11655-020-3094-7","article-title":"Effect and safety of hydroxysafflor yellow A for injection in patients with acute ischemic stroke of blood stasis syndrome: A phase II, multicenter, randomized, double-blind, multiple-dose, active-controlled clinical trial","volume":"26","author":"Hu","year":"2020","journal-title":"Chin. J. Integr. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.tox.2004.06.007","article-title":"The subchronic toxicity of hydroxysafflor yellow A of 90 days repeatedly intraperitoneal injections in rats","volume":"203","author":"Liu","year":"2004","journal-title":"Toxicology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1080\/01480545.2026.2626758","article-title":"Developmental and reproductive toxicity studies of Hydroxysafflor Yellow a in Sprague-Dawley rats","volume":"49","author":"Qiu","year":"2026","journal-title":"Drug Chem. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jchromb.2016.01.023","article-title":"UFLC-Q-TOF\/MS based screening and identification of the metabolites in plasma, bile, urine and feces of normal and blood stasis rats after oral administration of hydroxysafflor yellow A","volume":"1012\u20131013","author":"Jin","year":"2016","journal-title":"J. Chromatogr. B"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.jep.2013.12.025","article-title":"Effects of hydroxysafflor yellow A on the activity and mRNA expression of four CYP isozymes in rats","volume":"151","author":"Xu","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111023","DOI":"10.1016\/j.exer.2026.111023","article-title":"Diabetic Retinopathy: Research Advances in Canonical Cellular Pathways and Emerging Mechanisms","volume":"268","author":"Wu","year":"2026","journal-title":"Exp. Eye Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mimura, T., and Noma, H. (2025). Oxidative stress in diabetic retinopathy: A comprehensive review of mechanisms, biomarkers, and therapeutic perspectives. Antioxidants, 14.","DOI":"10.3390\/antiox14101204"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"He, W., Tang, P., and Lv, H. (2025). Targeting oxidative stress in diabetic retinopathy: Mechanisms, pathology, and novel treatment approaches. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1571576"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain","volume":"13","author":"Itoh","year":"1999","journal-title":"Genes Dev."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Yang, Y., and Zou, H. (2025). Research progress on Nrf2 intervention in the treatment of diabetic retinopathy. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1587231"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kinuthia, U.M., Wolf, A., and Langmann, T. (2020). Microglia and inflammatory responses in diabetic retinopathy. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.564077"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"R\u00fcbsam, A., Parikh, S., and Fort, P.E. (2018). Role of inflammation in diabetic retinopathy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040942"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3892\/mmr.2025.13657","article-title":"Role of the NLRP3 inflammasome in diabetes and its complications","volume":"32","author":"Jiao","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"114040","DOI":"10.1016\/j.intimp.2025.114040","article-title":"Hydroxysafflor yellow A attenuates the inflammatory response in cerebral ischemia\u2013reperfusion injured mice by regulating microglia polarization per SIRT1-mediated HMGB1\/NF-\u03baB signaling pathway","volume":"147","author":"Yao","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Maugeri, G., Bucolo, C., Drago, F., Rossi, S., Di Rosa, M., Imbesi, R., D\u2019Agata, V., and Giunta, S. (2021). Attenuation of high glucose-induced damage in RPE cells through p38 MAPK signaling pathway inhibition. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.684680"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1167\/iovs.09-3674","article-title":"Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function","volume":"51","author":"Du","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_51","first-page":"3349","article-title":"Involvement of caspase-3 in photoreceptor cell apoptosis induced by in vivo blue light exposure","volume":"43","author":"Wu","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1167\/iovs.06-1258","article-title":"Caspase-dependent apoptosis in light-induced retinal degeneration","volume":"48","author":"Perche","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"153532","DOI":"10.1016\/j.phymed.2021.153532","article-title":"Hydroxysafflor yellow A alleviates cerebral ischemia reperfusion injury by suppressing apoptosis via mitochondrial permeability transition pore","volume":"85","author":"Huang","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Yu, L., Jin, Z., Li, M., Liu, H., Tao, J., Xu, C., Wang, L., and Zhang, Q. (2022). Protective potential of hydroxysafflor yellow A in cerebral ischemia and reperfusion injury: An overview of evidence from experimental studies. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1063035"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"108107","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.108107","article-title":"Hydroxysafflor Yellow A promotes angiogenesis of brain microvascular endothelial cells from ischemia\/reperfusion injury via glycolysis pathway in vitro","volume":"34","author":"Ruan","year":"2025","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"116268","DOI":"10.1016\/j.jep.2023.116268","article-title":"Hydroxysafflor yellow a confers neuroprotection against acute traumatic brain injury by modulating neuronal autophagy to inhibit NLRP3 inflammasomes","volume":"308","author":"Lai","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ye, J., Lu, S., Wang, M., Ge, W., Liu, H., Qi, Y., Fu, J., Zhang, Q., Zhang, B., and Sun, G. (2020). Hydroxysafflor Yellow A Protects Against Myocardial Ischemia\/Reperfusion Injury via Suppressing NLRP3 Inflammasome and Activating Autophagy. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01170"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2021.12.262","article-title":"Hydroxysafflor yellow A and anhydrosafflor yellow B alleviate ferroptosis and parthanatos in PC12 cells injured by OGD\/R","volume":"179","author":"Chen","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Venkatesan, A., and Bernstein, A.M. (2025). Protein misfolding and mitochondrial dysfunction in glaucoma. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1595121"},{"key":"ref_60","first-page":"684","article-title":"Overexpression of hGDF15 in retina of transgenic mice is associated with retinal ganglion cell neuroprotection in a murine glaucoma model of increased intraocular pressure","volume":"65","author":"Zhang","year":"2024","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Mimura, T., and Noma, H. (2025). Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets. Antioxidants, 14.","DOI":"10.3390\/antiox14101251"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"20570","DOI":"10.1074\/jbc.M114.565457","article-title":"The retinal pigment epithelium utilizes fatty acids for ketogenesis","volume":"289","author":"Adijanto","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_63","first-page":"1981","article-title":"The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells","volume":"41","author":"Sparrow","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e14319","DOI":"10.7554\/eLife.14319","article-title":"Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration","volume":"5","author":"Kurihara","year":"2016","journal-title":"eLife"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"100167","DOI":"10.1016\/j.xops.2022.100167","article-title":"Age-Related Maculopathy Susceptibility 2 and Complement Factor H Polymorphism and Intraocular Complement Activation in Neovascular Age-Related Macular Degeneration","volume":"2","author":"Kato","year":"2022","journal-title":"Ophthalmol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1167\/iovs.12-9712","article-title":"Retinal ganglion cell morphology after optic nerve crush and experimental glaucoma","volume":"53","author":"Kalesnykas","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1167\/iovs.09-3947","article-title":"The microbead occlusion model: A paradigm for induced ocular hypertension in rats and mice","volume":"51","author":"Sappington","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B 3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1021\/acs.molpharmaceut.8b01319","article-title":"Fenofibrate-Loaded Biodegradable Nanoparticles for the Treatment of Experimental Diabetic Retinopathy and Neovascular Age-Related Macular Degeneration","volume":"16","author":"Qiu","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15296","DOI":"10.1038\/ncomms15296","article-title":"Plastic roles of pericytes in the blood-retinal barrier","volume":"8","author":"Park","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Varela-Fern\u00e1ndez, R., D\u00edaz-Tom\u00e9, V., Luaces-Rodr\u00edguez, A., Conde-Penedo, A., Garc\u00eda-Otero, X., Luzardo-\u00c1lvarez, A., Fern\u00e1ndez-Ferreiro, A., and Otero-Espinar, F.J. (2020). Drug delivery to the posterior segment of the eye: Biopharmaceutic and pharmacokinetic considerations. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12030269"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"103037","DOI":"10.1016\/j.fbio.2023.103037","article-title":"Transepithelial transport characteristics of Hydroxysafflor yellow A across cellular monolayers and the effects of the influx and efflux transporters","volume":"55","author":"Tang","year":"2023","journal-title":"Food Biosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/bmc.769","article-title":"Determination of hydroxysafflor yellow A in rat plasma and tissues by high-performance liquid chromatography after oral administration of safflower extract or safflor yellow","volume":"21","author":"Li","year":"2007","journal-title":"Biomed. Chromatogr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"19225","DOI":"10.1021\/acsomega.2c00457","article-title":"Oral bioavailability-enhancing and anti-obesity effects of hydroxysafflor yellow A in natural deep eutectic solvent","volume":"7","author":"Gao","year":"2022","journal-title":"ACS Omega"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhong, C., Wang, Q., Zhang, J., Zhao, H., Huang, Y., Zhao, D., and Yang, J. (2023). Nanoemulsions of hydroxysafflor yellow a for enhancing physicochemical and in vivo performance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108658"},{"key":"ref_76","first-page":"2108557","article-title":"Pharmacological Activities of Safflower Yellow and Its Clinical Applications","volume":"2022","author":"Chen","year":"2022","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/jps.2600620712","article-title":"Lacrimal and Instilled Fluid Dynamics in Rabbit Eyes","volume":"62","author":"Chrai","year":"1973","journal-title":"J. Pharm. Sci."},{"key":"ref_78","first-page":"584","article-title":"Importance of the noncorneal absorption route in topical ophthalmic drug delivery","volume":"26","author":"Ahmed","year":"1985","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s13318-016-0319-4","article-title":"Ocular Drug Distribution After Topical Administration: Population Pharmacokinetic Model in Rabbits","volume":"42","author":"Djebli","year":"2016","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40662-021-00239-1","article-title":"Neurovascular unit in diabetic retinopathy: Pathophysiological roles and potential therapeutical targets","volume":"8","author":"Nian","year":"2021","journal-title":"Eye Vis."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ren, J., Zhang, S., Pan, Y., Jin, M., Li, J., Luo, Y., Sun, X., and Li, G. (2022). Diabetic retinopathy: Involved cells, biomarkers, and treatments. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.953691"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.visres.2017.02.006","article-title":"Effects of diabetic retinopathy on the barrier functions of the retinal pigment epithelium","volume":"139","author":"Xia","year":"2017","journal-title":"Vis. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"12151","DOI":"10.1038\/s41598-021-91584-7","article-title":"Comparative transcriptome analysis of inner blood-retinal barrier and blood\u2013brain barrier in rats","volume":"11","author":"Li","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/bph.13376","article-title":"Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier","volume":"173","author":"Chapy","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4807","DOI":"10.1167\/iovs.08-3148","article-title":"Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits","volume":"50","author":"Nomoto","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2403142","DOI":"10.1002\/adfm.202403142","article-title":"Liposome-Based Permeable Eyedrops for Effective Posterior Segment Drug Delivery","volume":"34","author":"Wang","year":"2024","journal-title":"Adv. Funct. Mater."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1089\/jop.2021.0090","article-title":"Suprachoroidal Injection of Triamcinolone Acetonide Suspension: Ocular Pharmacokinetics and Distribution in Rabbits Demonstrates High and Durable Levels in the Chorioretina","volume":"38","author":"Muya","year":"2022","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.2147\/OPTH.S409103","article-title":"Through the Eyes of Patients: Understanding Treatment Burden of Intravitreal Anti-VEGF Injections for nAMD Patients in Norway","volume":"17","author":"Reitan","year":"2023","journal-title":"Clin. Ophthalmol."},{"key":"ref_89","first-page":"100947","article-title":"Intravitreal long-term sustained ranibizumab delivery using injectable microgel-embedded hydrogel","volume":"19","author":"Lee","year":"2024","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.2147\/DDDT.S374061","article-title":"Development and Evaluation of Puerarin Loaded-Albumin Nanoparticles Thermoresponsive in situ Gel for Ophthalmic Delivery","volume":"16","author":"Hu","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"104292","DOI":"10.1016\/j.jddst.2023.104292","article-title":"Development of Forskolin and rutin-loaded polymeric nanoparticles for enhancement of topical ocular delivery: Optimization, in-vitro, ex-vivo, and toxicity evaluation","volume":"82","author":"Dahiya","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5846","DOI":"10.1002\/jsfa.13407","article-title":"Formulation of hesperidin-loaded in situ gel for ocular drug delivery: A comprehensive study","volume":"104","author":"Polat","year":"2024","journal-title":"J. Sci. Food Agric."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"762","DOI":"10.29228\/jrp.737","article-title":"In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization","volume":"28","author":"Siafaka","year":"2024","journal-title":"J. Res. Pharm."},{"key":"ref_94","first-page":"11616","article-title":"Therapeutic Effect of Baicalin-Loaded Thermosensitive Liposomal Hydrogel in Autoimmune Uveitis","volume":"11","author":"Zhu","year":"2026","journal-title":"ACS Omega"},{"key":"ref_95","unstructured":"U.S. Food and Drug Administration (2018). Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation; Guidance for Industry; Availability. Fed. Regist., 83, 14642\u201314643."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"122209","DOI":"10.1016\/j.ijpharm.2022.122209","article-title":"Advances in in-vitro bioequivalence testing methods for complex ophthalmic generic products","volume":"627","author":"Renukuntla","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1089\/jop.2022.0184","article-title":"Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent","volume":"39","author":"Sheeler","year":"2023","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"114260","DOI":"10.1016\/j.ejpb.2024.114260","article-title":"Comprehensive ocular and systemic pharmacokinetics of dexamethasone after subconjunctival and intravenous injections in rabbits","volume":"198","author":"Valtari","year":"2024","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1021\/acs.molpharmaceut.8b00038","article-title":"Binding of Small Molecule Drugs to Porcine Vitreous Humor","volume":"15","author":"Reunanen","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1177\/2472555217724780","article-title":"Application of Imaging Mass Spectrometry to Assess Ocular Drug Transit","volume":"22","author":"Grove","year":"2017","journal-title":"SLAS Discov. Adv. Sci. Drug Discov."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"4443","DOI":"10.1039\/C8FO00732B","article-title":"Hydroxysafflor yellow A (HSYA) targets the NF-\u03baB and MAPK pathways and ameliorates the development of osteoarthritis","volume":"9","author":"Hu","year":"2018","journal-title":"Food Funct."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"8172706","DOI":"10.1155\/2016\/8172706","article-title":"Hydroxysafflor Yellow A Inhibits LPS-Induced NLRP3 Inflammasome Activation via Binding to Xanthine Oxidase in Mouse RAW264.7 Macrophages","volume":"2016","author":"Xu","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Ge, C., Peng, Y., Li, J., Wang, L., Zhu, X., Wang, N., Yang, D., Zhou, X., and Chang, D. (2023). Hydroxysafflor Yellow a Alleviates Acute Myocardial Ischemia\/Reperfusion Injury in Mice by Inhibiting Ferroptosis via the Activation of the HIF-1\u03b1\/SLC7A11\/GPX4 Signaling Pathway. Nutrients, 15.","DOI":"10.3390\/nu15153411"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Yang, Y., Lin, Y., Han, Z., Wang, B., Zheng, W., and Wei, L. (2024). Ferroptosis: A novel mechanism of cell death in ophthalmic conditions. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1440309"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.biopha.2018.10.193","article-title":"Safety, pharmacokinetics, and prevention effect of intraocular crocetin in proliferative vitreoretinopathy","volume":"109","author":"Wang","year":"2019","journal-title":"Biomed. Pharmacother."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/7\/865\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:31:19Z","timestamp":1783690279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/7\/865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":105,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["antiox15070865"],"URL":"https:\/\/doi.org\/10.3390\/antiox15070865","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]}}}