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<p>Lactate accumulation is a hallmark and contributing factor of intervertebral disc degeneration (IVDD), while the role of protein lactylation caused by lactate accumulation in IVDD remains unclear. Via metabolomics, single-cell RNA-sequencing analysis, and lactylation proteomics, we reveal the lactylome landscape in IVDD and identified superoxide dismutase 1 (SOD1) lactylation at lysine 123 (SOD1<sup>K123la</sup>) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1<sup>K123R</sup> mutant male rats, and in silico molecular dynamics simulations, we find that SOD1<sup>K123la</sup> alters SOD1 conformation and impairs its enzymatic activity, and induces oxidative damage, and activates p53 pathway in nucleus pulposus cells (NPCs). Notably, we identify a small molecule ZL-01 that inhibits SOD1<sup>K123la</sup>. NPC-targeted delivery of ZL-01 via collagen type II-targeted peptide-modified extracellular vesicles alleviated IVDD in male rats. Together, these findings clarify the mechanism by which SOD1<sup>K123la</sup> promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.</p>

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SOD1 lactylation impair its enzymatic activity by conformational change to aggravate intervertebral disc degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • Yuyao Zhang,
  • Yu Zhai,
  • Chao Liu,
  • Minghang Chen,
  • Yang Zhang,
  • Zhiqun Bian,
  • Xian Chang,
  • Zhilei Hu,
  • Jianmin Li,
  • Chao Zhang,
  • Zhenhong Ni,
  • Yangli Xie,
  • Lin Chen,
  • Minghan Liu,
  • Changqing Li

摘要

Lactate accumulation is a hallmark and contributing factor of intervertebral disc degeneration (IVDD), while the role of protein lactylation caused by lactate accumulation in IVDD remains unclear. Via metabolomics, single-cell RNA-sequencing analysis, and lactylation proteomics, we reveal the lactylome landscape in IVDD and identified superoxide dismutase 1 (SOD1) lactylation at lysine 123 (SOD1K123la) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1K123R mutant male rats, and in silico molecular dynamics simulations, we find that SOD1K123la alters SOD1 conformation and impairs its enzymatic activity, and induces oxidative damage, and activates p53 pathway in nucleus pulposus cells (NPCs). Notably, we identify a small molecule ZL-01 that inhibits SOD1K123la. NPC-targeted delivery of ZL-01 via collagen type II-targeted peptide-modified extracellular vesicles alleviated IVDD in male rats. Together, these findings clarify the mechanism by which SOD1K123la promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.