Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway
BackgroundNeuronal senescence is a common pathological feature of various neurodegenerative diseases, with ferroptosis playing a significant role. This study aims to investigate the role of ErbB4 receptor activation in preventing D-Galactose (D-gal)-induced neuronal senescence.MethodsMice subjected...
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Frontiers Media S.A.
2025-01-01
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| author | Ji-Ji Dao Ji-Ji Dao Wei Zhang Wei Zhang Chong Liu Chong Liu Qian Li Qian Li Chen-Meng Qiao Chen-Meng Qiao Chun Cui Chun Cui Yan-Qin Shen Yan-Qin Shen Shuang-Xi Chen Shuang-Xi Chen Wei-Jiang Zhao Wei-Jiang Zhao |
| author_facet | Ji-Ji Dao Ji-Ji Dao Wei Zhang Wei Zhang Chong Liu Chong Liu Qian Li Qian Li Chen-Meng Qiao Chen-Meng Qiao Chun Cui Chun Cui Yan-Qin Shen Yan-Qin Shen Shuang-Xi Chen Shuang-Xi Chen Wei-Jiang Zhao Wei-Jiang Zhao |
| author_sort | Ji-Ji Dao |
| collection | DOAJ |
| description | BackgroundNeuronal senescence is a common pathological feature of various neurodegenerative diseases, with ferroptosis playing a significant role. This study aims to investigate the role of ErbB4 receptor activation in preventing D-Galactose (D-gal)-induced neuronal senescence.MethodsMice subjected to D-gal-induced aging were administered a small molecule ErbB4 receptor agonist (E4A), identified via virtual screening, melatonin, or a combination of both. Behavioral assessments were conducted to evaluate therapeutic efficacy in memory and cognitive functions. Immunofluorescence staining, western blot, and biochemical assays were primarily employed to assess changes in both senescence- and ferroptosis-related molecules in mouse hippocampal tissues in response to each treatment. Additionally, mouse hippocampal HT22 neuronal cell cultures were utilized to corroborate the in vivo findings.ResultsThe targeted activation of ErbB4 receptor by E4A significantly ameliorated the behavioral deficits induced by D-gal in mice, demonstrating an effect comparable to that of melatonin, a natural inhibitor of in vivo senescence and ferroptosis. Both E4A and melatonin mitigated D-gal-induced aging in hippocampal neurons of mice. This was evidenced by the upregulation of Lamin B1 and the downregulation of P53, P21, P16, GFAP, and Iba-1 expression levels. Moreover, D-gal treatment markedly decreased the protein expression of the ferroptosis inhibitor Nrf2 while augmenting the expression of the ferroptosis promoter TFRC. These alterations were partially reversed by the individual administration of E4A and melatonin. In vitro studies further corroborated that D-gal treatment significantly and concurrently induced the expression of senescence markers and ferroptosis promoters. However, both E4A and melatonin were able to significantly reverse these changes. Additionally, E4A markedly ameliorated Erastin-induced ferroptosis in mouse hippocampal neuronal cells.ConlusionOur findings suggest that targeted activation of ErbB4 receptor may be a viable strategy for treating neuronal senescence by inhibiting ferroptosis, thereby offering a potential therapeutic avenue for senescence-associated neurodegenerative diseases. |
| format | Article |
| id | doaj-art-d1d2f29bb3504ca8bcf4a40181da1b83 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-d1d2f29bb3504ca8bcf4a40181da1b832025-01-31T06:40:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011610.3389/fphar.2025.15286041528604Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathwayJi-Ji Dao0Ji-Ji Dao1Wei Zhang2Wei Zhang3Chong Liu4Chong Liu5Qian Li6Qian Li7Chen-Meng Qiao8Chen-Meng Qiao9Chun Cui10Chun Cui11Yan-Qin Shen12Yan-Qin Shen13Shuang-Xi Chen14Shuang-Xi Chen15Wei-Jiang Zhao16Wei-Jiang Zhao17Cell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaCell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaDepartment of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, Guizhou, ChinaCell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaCell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaLaboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaLaboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaLaboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaThe First Affiliated Hospital, Department of Neurology, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaClinical Research Center for Immune-Related Encephalopathy in Hunan Province, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaCell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaMOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, ChinaBackgroundNeuronal senescence is a common pathological feature of various neurodegenerative diseases, with ferroptosis playing a significant role. This study aims to investigate the role of ErbB4 receptor activation in preventing D-Galactose (D-gal)-induced neuronal senescence.MethodsMice subjected to D-gal-induced aging were administered a small molecule ErbB4 receptor agonist (E4A), identified via virtual screening, melatonin, or a combination of both. Behavioral assessments were conducted to evaluate therapeutic efficacy in memory and cognitive functions. Immunofluorescence staining, western blot, and biochemical assays were primarily employed to assess changes in both senescence- and ferroptosis-related molecules in mouse hippocampal tissues in response to each treatment. Additionally, mouse hippocampal HT22 neuronal cell cultures were utilized to corroborate the in vivo findings.ResultsThe targeted activation of ErbB4 receptor by E4A significantly ameliorated the behavioral deficits induced by D-gal in mice, demonstrating an effect comparable to that of melatonin, a natural inhibitor of in vivo senescence and ferroptosis. Both E4A and melatonin mitigated D-gal-induced aging in hippocampal neurons of mice. This was evidenced by the upregulation of Lamin B1 and the downregulation of P53, P21, P16, GFAP, and Iba-1 expression levels. Moreover, D-gal treatment markedly decreased the protein expression of the ferroptosis inhibitor Nrf2 while augmenting the expression of the ferroptosis promoter TFRC. These alterations were partially reversed by the individual administration of E4A and melatonin. In vitro studies further corroborated that D-gal treatment significantly and concurrently induced the expression of senescence markers and ferroptosis promoters. However, both E4A and melatonin were able to significantly reverse these changes. Additionally, E4A markedly ameliorated Erastin-induced ferroptosis in mouse hippocampal neuronal cells.ConlusionOur findings suggest that targeted activation of ErbB4 receptor may be a viable strategy for treating neuronal senescence by inhibiting ferroptosis, thereby offering a potential therapeutic avenue for senescence-associated neurodegenerative diseases.https://www.frontiersin.org/articles/10.3389/fphar.2025.1528604/fullErbB4 receptorsmall moleculesenescenceD-galactosehippocampusneuron |
| spellingShingle | Ji-Ji Dao Ji-Ji Dao Wei Zhang Wei Zhang Chong Liu Chong Liu Qian Li Qian Li Chen-Meng Qiao Chen-Meng Qiao Chun Cui Chun Cui Yan-Qin Shen Yan-Qin Shen Shuang-Xi Chen Shuang-Xi Chen Wei-Jiang Zhao Wei-Jiang Zhao Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway Frontiers in Pharmacology ErbB4 receptor small molecule senescence D-galactose hippocampus neuron |
| title | Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway |
| title_full | Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway |
| title_fullStr | Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway |
| title_full_unstemmed | Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway |
| title_short | Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway |
| title_sort | targeted erbb4 receptor activation prevents d galactose induced neuronal senescence via inhibiting ferroptosis pathway |
| topic | ErbB4 receptor small molecule senescence D-galactose hippocampus neuron |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1528604/full |
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