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

Abstract

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) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1mutant male rats, and in silico molecular dynamics simulations, we find that SOD1alters 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. 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 SOD1promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.