Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4
Diabetic retinopathy (DR), a leading cause of vision impairment worldwide, is characterized by early neuronal damage in the retina, termed diabetic neuropathy in the retina (DNR). This condition is marked by neuronal apoptosis and glial activation. Müller glia are retinal cells highly susceptible to...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/jdr/1924668 |
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| author | Xinlu Li Bai Li Defei Feng Han Hu Binyang Tang Jingying Yang Huaiyan Jiang Li Li Xiaojing Dong Ninghua Ni Yan Mei |
| author_facet | Xinlu Li Bai Li Defei Feng Han Hu Binyang Tang Jingying Yang Huaiyan Jiang Li Li Xiaojing Dong Ninghua Ni Yan Mei |
| author_sort | Xinlu Li |
| collection | DOAJ |
| description | Diabetic retinopathy (DR), a leading cause of vision impairment worldwide, is characterized by early neuronal damage in the retina, termed diabetic neuropathy in the retina (DNR). This condition is marked by neuronal apoptosis and glial activation. Müller glia are retinal cells highly susceptible to diabetic metabolic stress that may undergo ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, the role of ferroptosis in DNR pathogenesis remains undefined. In this study, we investigated Müller cell injury under high-glucose and palmitic acid (HGP) conditions. The retinal tissues were obtained from normal rabbits and alloxan-induced diabetic rabbits. HGP exposure significantly reduced Müller cell viability, induced cell cycle arrest, and elevated proinflammatory cytokines. Ultrastructural analysis revealed mitochondrial damage, accompanied by decreased glutathione (GSH) and increased malondialdehyde (MDA), ferrous iron (Fe2+), and reactive oxygen species (ROS) levels. RNA sequencing (RNA-Seq) identified SQSTM1 as a ferroptosis-related differentially expressed gene, which was significantly upregulated in HGP-treated cells. In vivo, DNR rabbits exhibited oxidative stress, iron dysregulation, and elevated SQSTM1 expression that colocalized with GFAP+ Müller cells. Single-cell RNA-Seq of human proliferative diabetic retinopathy (PDR) retinas confirmed elevated SQSTM1 expression in Müller cells compared to healthy control (HC) retinas. Mechanistically, SQSTM1 knockdown attenuated ferroptosis, oxidative stress, and HGP-induced injury, while its overexpression exacerbated ferroptosis via ACSL4 upregulation. Overall, our findings suggest that SQSTM1 may serve as a critical mediator linking Müller cell dysfunction and ferroptosis in DNR pathogenesis, offering a novel potential therapeutic target. |
| format | Article |
| id | doaj-art-1a4e2b67f5724f58805188a91c8e32d1 |
| institution | Kabale University |
| issn | 2314-6753 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-1a4e2b67f5724f58805188a91c8e32d12025-08-21T00:00:04ZengWileyJournal of Diabetes Research2314-67532025-01-01202510.1155/jdr/1924668Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4Xinlu Li0Bai Li1Defei Feng2Han Hu3Binyang Tang4Jingying Yang5Huaiyan Jiang6Li Li7Xiaojing Dong8Ninghua Ni9Yan Mei10Faculty of Life Science and TechnologyDepartment of OphthalmologyAffiliated Dehong People’s Hospital of Kunming Medical UniversityChangsha Aier Eye HospitalThe First Affiliated Hospital of Chongqing Medical UniversityDepartment of OphthalmologyDepartment of OphthalmologyCenter for Clinical Medicine ResearchDepartment of OphthalmologyDepartment of OphthalmologyDepartment of OphthalmologyDiabetic retinopathy (DR), a leading cause of vision impairment worldwide, is characterized by early neuronal damage in the retina, termed diabetic neuropathy in the retina (DNR). This condition is marked by neuronal apoptosis and glial activation. Müller glia are retinal cells highly susceptible to diabetic metabolic stress that may undergo ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, the role of ferroptosis in DNR pathogenesis remains undefined. In this study, we investigated Müller cell injury under high-glucose and palmitic acid (HGP) conditions. The retinal tissues were obtained from normal rabbits and alloxan-induced diabetic rabbits. HGP exposure significantly reduced Müller cell viability, induced cell cycle arrest, and elevated proinflammatory cytokines. Ultrastructural analysis revealed mitochondrial damage, accompanied by decreased glutathione (GSH) and increased malondialdehyde (MDA), ferrous iron (Fe2+), and reactive oxygen species (ROS) levels. RNA sequencing (RNA-Seq) identified SQSTM1 as a ferroptosis-related differentially expressed gene, which was significantly upregulated in HGP-treated cells. In vivo, DNR rabbits exhibited oxidative stress, iron dysregulation, and elevated SQSTM1 expression that colocalized with GFAP+ Müller cells. Single-cell RNA-Seq of human proliferative diabetic retinopathy (PDR) retinas confirmed elevated SQSTM1 expression in Müller cells compared to healthy control (HC) retinas. Mechanistically, SQSTM1 knockdown attenuated ferroptosis, oxidative stress, and HGP-induced injury, while its overexpression exacerbated ferroptosis via ACSL4 upregulation. Overall, our findings suggest that SQSTM1 may serve as a critical mediator linking Müller cell dysfunction and ferroptosis in DNR pathogenesis, offering a novel potential therapeutic target.http://dx.doi.org/10.1155/jdr/1924668 |
| spellingShingle | Xinlu Li Bai Li Defei Feng Han Hu Binyang Tang Jingying Yang Huaiyan Jiang Li Li Xiaojing Dong Ninghua Ni Yan Mei Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4 Journal of Diabetes Research |
| title | Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4 |
| title_full | Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4 |
| title_fullStr | Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4 |
| title_full_unstemmed | Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4 |
| title_short | Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4 |
| title_sort | upregulation of sqstm1 regulates ferroptosis and oxidative stress in muller cells of the diabetic neural retina by modulating acsl4 |
| url | http://dx.doi.org/10.1155/jdr/1924668 |
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