2. Academic Validation
  3. Oxidative stress activates YAP/TEAD1/NCOA4 axis to promote ferroptosis of endplate chondrocytes and aggravate intervertebral disc degeneration

Oxidative stress activates YAP/TEAD1/NCOA4 axis to promote ferroptosis of endplate chondrocytes and aggravate intervertebral disc degeneration

  • J Orthop Translat. 2025 Jul 12:54:8-25. doi: 10.1016/j.jot.2025.07.001.
Heran Wang 1,  Xiaodong Liu 1,  Xingzhi Jing 1,  Bofei Zhang 2,  Xin Liu 3,  Xiaoyang Liu 1,  Fei Jia 1,  Cheng Su 1,  Wenchao Wang 1,  Xingang Cui 1
Affiliations

Affiliations

  • 1 Department of Spine Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250000, China.
  • 2 Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
  • 3 Department of Radiation Physics, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.
PMID: 40688343 DOI: 10.1016/j.jot.2025.07.001
Abstract

Background: Intervertebral disc degeneration (IDD) is a major cause of low back pain, with cartilaginous endplate (CEP) degeneration playing a critical role. While Yes-associated protein (YAP) and its involvement in CEP degeneration and Ferroptosis remain unclear. This study aimed to investigate the regulatory role of YAP in CEP Ferroptosis and its underlying mechanisms.

Methods: YAP expression was analyzed in human CEP tissues and mouse LSI models. CEP cells were treated with Verteporfin or YAP-siRNA. Ferroptosis was assessed by measuring iron levels, lipid peroxidation, GSH content, and viability assays. Molecular mechanisms were elucidated using CUT&RUN-qPCR, dual-LUC, and immunofluorescence colocalization. Verteporfin (VP) therapeutic efficacy was evaluated in LSI mice.

Results: YAP knockdown attenuated oxidative stress-induced CEP chondrocyte degeneration and Ferroptosis features. Mechanistically, we identified that oxidative stress-induced CEP chondrocyte degeneration involves ferritinophagy, which is regulated by the YAP/TEAD1 signaling axis through transcriptional control of nuclear coactivator 4 (NCOA4). Treatment with verteporfin, a YAP/TEAD1 axis inhibitor, effectively reduced CEP chondrocyte degeneration and IDD progression by targeting NCOA4-mediated ferritinophagy.

Conclusion: Through detailed molecular and cellular analyses, we revealed that the YAP/TEAD1/NCOA4 signaling axis plays a crucial role in regulating CEP chondrocyte Ferroptosis and IDD development. These findings not only enhance our understanding of IDD pathogenesis but also suggest that targeting the YAP/TEAD1/NCOA4 axis could be a promising therapeutic strategy for treating IDD.

The translational potential of this article: This study reveals YAP as a novel therapeutic target for intervertebral disc degeneration by regulating Ferroptosis in cartilage endplate cells, which provides a novel strategy in the prevention of IDD.

Keywords

Cartilage endplate; Ferroptosis; Intervertebral disc degeneration; NCOA4; YAP/TEAD1.

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