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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1528604

Targeted ErbB4 receptor activation prevents D-Galactose-induced neuronal senescence via inhibiting ferroptosis pathway

Provisionally accepted
Ji-ji Dao Ji-ji Dao 1Wei Zhang Wei Zhang 1Chong Liu Chong Liu 1Qian Li Qian Li 1Chen-Meng Qiao Chen-Meng Qiao 1Chun Cui Chun Cui 1Yan-Qin Shen Yan-Qin Shen 1Shuang-xi Chen Shuang-xi Chen 2Wei-jiang Zhao Wei-jiang Zhao 1,3*
  • 1 Wuxi Medical College, Jiangnan University, Wuxi, China
  • 2 University of South China, Hengyang, Hunan Province, China
  • 3 Jiangnan University, Wuxi, Jiangsu Province, China

The final, formatted version of the article will be published soon.

    Studies have demonstrated that neuronal senescence is a prevalent pathological characteristic 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. Utilizing a small molecule ErbB4 receptor agonist (E4A) identified through virtual screening, it was observed that activation of the ErbB4 receptor significantly ameliorated the behavioral deficits induced by D-gal in mice. This effect is comparable to that of melatonin, a natural inhibitor of in vivo senescence and ferroptosis. Subsequent research demonstrated that both the ErbB4 receptor agonist and melatonin (MLT) ameliorate Dgal-induced aging in hippocampal neurons of mice. This is 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 the E4A and MLT. 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 MLT were able to significantly reverse these changes. Additionally, E4A markedly ameliorated Erastin-induced ferroptosis in mouse hippocampal neuronal cells. Collectively, our data suggest that targeted activation of the 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.

    Keywords: ErbB4 receptor, small molecule, senescence, D-galactose, Neuron

    Received: 15 Nov 2024; Accepted: 03 Jan 2025.

    Copyright: © 2025 Dao, Zhang, Liu, Li, Qiao, Cui, Shen, Chen and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Wei-jiang Zhao, Wuxi Medical College, Jiangnan University, Wuxi, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.