髓核细胞衰老是促进椎间盘退变的重要因素。我们前期发表的研究中发现NOX4相关的氧化应激可以诱导髓核细胞的衰老，但其深入机制并未完全探明。最新研究报道了EZH2是调控细胞衰老的关键基因。我们前期的实验发现髓核细胞中EZH2受到NOX4的调控并参与髓核细胞衰老的调控。同时，我们也发现髓核细胞中的NOX4也受到EZH2的调控。所以，我们推测髓核细胞中存在NOX4-EZH2调控环路参与髓核细胞衰老的调控。此外，结合最新研究和前期实验，我们进一步猜测NOX4和EZH2的相互调控与WNT-MYC，DDR-ATM，MAPK和NF-κB信号以及H3K27的甲基化和乙酰化密切相关。本项目旨在通过对上述科学假设的探索，明确NOX4-EZH2相互调控的作用及其机制，并揭示这个由NOX4和EZH2构成的环路在调控髓核细胞氧化应激、衰老以及椎间盘退变发生发展中的关键角色，为椎间盘退变的预防和逆转提供新的潜在靶点。

The senescense of nucleus pulposus (NP) cells play a vital role in the pathogenesis of intervertebral disc degeneration (IDD). Our previous studies have reported that NADPH oxidase 4 (NOX4)-associated oxidative stress induces the premature senescense of NP cells. However, the deep insight into the mechanism remains unclear. EZH2 has been accepted as a crucial gene regulating cell senescense. We have found that EZH2 is regulated by NOX4 in NP cells, and is involved in regulating NP cell senescence. Meanwhile, we also found that NOX4 is regulated by EZH2 in NP cells. Therefore, we speculated that there is a NOX4-EZH2 feedback loop that is involved in the regulation of NP cell senescence. Furthermore, based on the recent studies and our results, we hypothesized that the interaction between NOX4 and EZH2 is associated with WNT-MYC, DDR-ATM, MAPK, NF-κB signaling pathways and the epigenetic modification of N-terminal 27th lysine (H3K27) on histone H3. The current program aims to clarify the roles of NOX4-EZH2 feedback loop in the regulation of oxidative stress in NP cells, NP cell senescence and IDD. Our investigations will provide a new potential target for the prevention and reverse of IDD.