DDX1 methylation mediated MATR3 splicing regulates intervertebral disc degeneration by initiating chromatin reprogramming

作者：Dingchao Zhu, Huaizhen Liang, Bide Tong, Zhi Du, Gaocai Li, Wei-Feng Zhang, Di Wu, Xingyu Zhou, Jie Lei, Xiaoguang Zhang, Liang Ma, Bingjin Wang, Xiaobo Feng, Kun Wang, Lei Tan, Yu Song, Yang Cao · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61486-7 · 被引用次数：13 · 研究领域：Spine and Intervertebral Disc Pathology、Orthopaedic implants and arthroplasty、Osteoarthritis Treatment and Mechanisms

Low back pain (LBP), primarily driven by intervertebral disc degeneration (IVDD), has become a core challenge in public health. DDX1, an RNA-binding protein, plays key roles in RNA metabolism but its function in IVDD remains unclear. We identify DDX1 as a substrate of methyltransferase EZH2, which methylates DDX1 at lysine 234 (K234), promoting IVDD in vitro and in vivo. EZH2 inhibition restores matrix homeostasis in nucleus pulposus (NP) cells and slows IVDD progression. Methylation at DDX1 K234 disrupts its interaction with splicing factors and RNA targets, promoting exon 14 skipping in MATR3. This truncated MATR3 disrupts nuclear architecture, increases chromatin accessibility, and activates signaling pathways such as Wnt, leading to NP cell senescence and apoptosis. Notably, delivery of MATR3-L-overexpressing mRNA via cationic lipid nanoparticles reduces NP cell degeneration and significantly alleviates IVDD, offering important insights into IVDD pathogenesis and potential therapeutic strategies. Here, the authors identify EZH2-mediated DDX1 K234 methylation as a driver of MATR3 mis-splicing, leading to senescence and apoptosis of NP cells, and propose lipid nanoparticle-based delivery of full-length MATR3 as a potential therapy for IVDD.