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<p>This study aimed to elucidate the role and underlying molecular mechanism of the Notch-1 pathway in regulating ferroptosis in retinal ganglion cells (RGCs) after ocular trauma, focusing on the NICD/YAP/EZH2 signaling axis. Bioinformatics analysis was performed on the GSE133563 dataset to identify differentially expressed genes (DEGs) and enriched pathways related to ocular trauma, ferroptosis and Notch signaling. In vivo, two traumatic optic neuropathy (TON) rat models were established and treated with Notch-1 inhibitor DAPT or Notch-1 knockdown/overexpression (KD/OE), followed by HE and TUNEL staining. In vitro, Western blot, immunofluorescence, ELISA and ChIP-qPCR were conducted to verify the transcriptional regulatory relationship within the NICD/Hes1/YAP/EZH2 axis. Flow cytometry was applied to detect cell apoptosis and total reactive oxygen species (DCFH-DA), and C11-BODIPY 581/591 fluorescence staining was performed to verify ferroptosis-specific lipid peroxidation. Rescue experiments were carried out using VPA (Notch-1 agonist), IAG933 (YAP inhibitor), EZH2 overexpression and Fer-1 (ferroptosis inhibitor). A total of 7611 DEGs were screened, enriched in autophagy, Notch signaling and ferroptosis pathways. Notch-1 was positively correlated with Hes1, while Hes1 was negatively correlated with EZH2. In vivo, DAPT and Notch-1 knockout exacerbated ganglion cell layer (GCL) damage and apoptosis in TON rats. In vitro, Notch-1 activation upregulated nuclear NICD, Hes1 and YAP and downregulated EZH2, validating the regulatory axis. Notch-1 activation elevated GPX4/SLC7A11 and SOD/GSH levels, reduced NOX4/NCOA4, autophagy-related proteins, ROS, MDA and Fe²⁺, and suppressed apoptosis and lipid peroxidation. The protective effects of VPA were abolished by IAG933 or EZH2 overexpression, while Fer-1 partially mitigated EZH2 overexpression-induced injury. Notch-1 activation protects RGCs from trauma-induced ferroptosis via the NICD/Hes1/YAP axis, which inhibits EZH2 expression and subsequently suppresses ferroptosis, oxidative stress and apoptosis. The NICD/Hes1/YAP/EZH2 axis serves as a vital endogenous protective mechanism and a promising therapeutic target for RGC loss after ocular trauma.</p>

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Notch-1 suppressed ocular trauma injury in ganglion cells via modulating NICD/YAP/EZH2 signaling induced ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Huipeng Miao,
  • Xinli Jiang,
  • Xiaokun Liu

摘要

This study aimed to elucidate the role and underlying molecular mechanism of the Notch-1 pathway in regulating ferroptosis in retinal ganglion cells (RGCs) after ocular trauma, focusing on the NICD/YAP/EZH2 signaling axis. Bioinformatics analysis was performed on the GSE133563 dataset to identify differentially expressed genes (DEGs) and enriched pathways related to ocular trauma, ferroptosis and Notch signaling. In vivo, two traumatic optic neuropathy (TON) rat models were established and treated with Notch-1 inhibitor DAPT or Notch-1 knockdown/overexpression (KD/OE), followed by HE and TUNEL staining. In vitro, Western blot, immunofluorescence, ELISA and ChIP-qPCR were conducted to verify the transcriptional regulatory relationship within the NICD/Hes1/YAP/EZH2 axis. Flow cytometry was applied to detect cell apoptosis and total reactive oxygen species (DCFH-DA), and C11-BODIPY 581/591 fluorescence staining was performed to verify ferroptosis-specific lipid peroxidation. Rescue experiments were carried out using VPA (Notch-1 agonist), IAG933 (YAP inhibitor), EZH2 overexpression and Fer-1 (ferroptosis inhibitor). A total of 7611 DEGs were screened, enriched in autophagy, Notch signaling and ferroptosis pathways. Notch-1 was positively correlated with Hes1, while Hes1 was negatively correlated with EZH2. In vivo, DAPT and Notch-1 knockout exacerbated ganglion cell layer (GCL) damage and apoptosis in TON rats. In vitro, Notch-1 activation upregulated nuclear NICD, Hes1 and YAP and downregulated EZH2, validating the regulatory axis. Notch-1 activation elevated GPX4/SLC7A11 and SOD/GSH levels, reduced NOX4/NCOA4, autophagy-related proteins, ROS, MDA and Fe²⁺, and suppressed apoptosis and lipid peroxidation. The protective effects of VPA were abolished by IAG933 or EZH2 overexpression, while Fer-1 partially mitigated EZH2 overexpression-induced injury. Notch-1 activation protects RGCs from trauma-induced ferroptosis via the NICD/Hes1/YAP axis, which inhibits EZH2 expression and subsequently suppresses ferroptosis, oxidative stress and apoptosis. The NICD/Hes1/YAP/EZH2 axis serves as a vital endogenous protective mechanism and a promising therapeutic target for RGC loss after ocular trauma.