Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration
Abstract Background Retinal degeneration is a leading cause of blindness worldwide. The induction of ferroptosis has been identified as an important mechanism contributing to the loss of photoreceptors in retinal degeneration. Lipocalin-2 (LCN2) exhibits iron-regulatory properties and may modulate c...
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BMC
2025-05-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01250-1 |
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| author | Wenyi Tang Ruyi Zhai Jun Ma Gezhi Xu |
| author_facet | Wenyi Tang Ruyi Zhai Jun Ma Gezhi Xu |
| author_sort | Wenyi Tang |
| collection | DOAJ |
| description | Abstract Background Retinal degeneration is a leading cause of blindness worldwide. The induction of ferroptosis has been identified as an important mechanism contributing to the loss of photoreceptors in retinal degeneration. Lipocalin-2 (LCN2) exhibits iron-regulatory properties and may modulate cell viability in various diseases. However, the effects of LCN2 on ferroptosis in retinal degeneration remain unclear. Methods A light-induced injury model using 661W photoreceptor cells and a light-induced retinal degeneration male rat model were established. LCN2 protein expression was assessed by western blotting. The effects of LCN2 on ferroptosis in vitro were investigated by using recombinant LCN2 protein (rLCN2) and small-interfering RNA (siRNA) targeting LCN2 (siLCN2). Fe2+, malondialdehyde (MDA), tripeptide glutathione (GSH) levels, and the expression of ferroptosis-associated proteins (solute carrier family 7 member 11 [SLC7A11] and glutathione peroxidase-4 [GPX4]) were measured. A phosphokinase array and western blotting were performed to elucidate the mechanisms underlying LCN2-modulated photoreceptor ferroptosis. Additionally, the protective effects of LCN2 knockdown using adeno-associated virus (AAV)-expressing short hairpin RNA (shRNA) targeting LCN2 (AAV-shRNA-LCN2) on retinal structure and function in vivo were evaluated by hematoxylin and eosin staining and electroretinography. Results LCN2 expression was significantly upregulated following light exposure. Treatment with rLCN2 significantly induced ferroptosis in photoreceptor cells, as shown by decreased cell viability, increased Fe2+ levels, inhibition of SLC7A11 and GPX4 expression, depletion of GSH, and enhanced MDA levels, whereas siLCN2 protected against these effects. Exposure of photoreceptor cells to rLCN2 activated c-Jun N-terminal kinase (JNK), and administration of the JNK inhibitor SP600125 protected photoreceptor cells from ferroptosis. Lastly, AAV-shRNA-LCN2 administration inhibited light-induced ferroptosis in the retina, and protected the retinal structure and function in vivo. Conclusion LCN2 is a key regulator of light-induced ferroptosis in photoreceptors by modulating the JNK pathway. Therefore, LCN2 presents a new target for the treatment of retinal degeneration. |
| format | Article |
| id | doaj-art-e482fdd886cc4ca2b99b39f1ad8004dc |
| institution | OA Journals |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Molecular Medicine |
| spelling | doaj-art-e482fdd886cc4ca2b99b39f1ad8004dc2025-08-20T02:25:11ZengBMCMolecular Medicine1528-36582025-05-0131111810.1186/s10020-025-01250-1Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degenerationWenyi Tang0Ruyi Zhai1Jun Ma2Gezhi Xu3Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan UniversityEye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan UniversityEye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan UniversityEye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan UniversityAbstract Background Retinal degeneration is a leading cause of blindness worldwide. The induction of ferroptosis has been identified as an important mechanism contributing to the loss of photoreceptors in retinal degeneration. Lipocalin-2 (LCN2) exhibits iron-regulatory properties and may modulate cell viability in various diseases. However, the effects of LCN2 on ferroptosis in retinal degeneration remain unclear. Methods A light-induced injury model using 661W photoreceptor cells and a light-induced retinal degeneration male rat model were established. LCN2 protein expression was assessed by western blotting. The effects of LCN2 on ferroptosis in vitro were investigated by using recombinant LCN2 protein (rLCN2) and small-interfering RNA (siRNA) targeting LCN2 (siLCN2). Fe2+, malondialdehyde (MDA), tripeptide glutathione (GSH) levels, and the expression of ferroptosis-associated proteins (solute carrier family 7 member 11 [SLC7A11] and glutathione peroxidase-4 [GPX4]) were measured. A phosphokinase array and western blotting were performed to elucidate the mechanisms underlying LCN2-modulated photoreceptor ferroptosis. Additionally, the protective effects of LCN2 knockdown using adeno-associated virus (AAV)-expressing short hairpin RNA (shRNA) targeting LCN2 (AAV-shRNA-LCN2) on retinal structure and function in vivo were evaluated by hematoxylin and eosin staining and electroretinography. Results LCN2 expression was significantly upregulated following light exposure. Treatment with rLCN2 significantly induced ferroptosis in photoreceptor cells, as shown by decreased cell viability, increased Fe2+ levels, inhibition of SLC7A11 and GPX4 expression, depletion of GSH, and enhanced MDA levels, whereas siLCN2 protected against these effects. Exposure of photoreceptor cells to rLCN2 activated c-Jun N-terminal kinase (JNK), and administration of the JNK inhibitor SP600125 protected photoreceptor cells from ferroptosis. Lastly, AAV-shRNA-LCN2 administration inhibited light-induced ferroptosis in the retina, and protected the retinal structure and function in vivo. Conclusion LCN2 is a key regulator of light-induced ferroptosis in photoreceptors by modulating the JNK pathway. Therefore, LCN2 presents a new target for the treatment of retinal degeneration.https://doi.org/10.1186/s10020-025-01250-1Lipocalin 2FerroptosisPhotoreceptorLight-induced retinal degenerationJNK |
| spellingShingle | Wenyi Tang Ruyi Zhai Jun Ma Gezhi Xu Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration Molecular Medicine Lipocalin 2 Ferroptosis Photoreceptor Light-induced retinal degeneration JNK |
| title | Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration |
| title_full | Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration |
| title_fullStr | Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration |
| title_full_unstemmed | Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration |
| title_short | Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration |
| title_sort | lipocalin 2 mediated ferroptosis as a target for protection against light induced photoreceptor degeneration |
| topic | Lipocalin 2 Ferroptosis Photoreceptor Light-induced retinal degeneration JNK |
| url | https://doi.org/10.1186/s10020-025-01250-1 |
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