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

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^K123la) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1^K123R mutant male rats, and in silico molecular dynamics simulations, we find that SOD1^K123la 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^K123la. 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^K123la promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.