Integrated multi-omics and functional analyses identify the renin-angiotensin system dysregulation as a central driver of lumbar disc herniation

Introduction Lumbar disc herniation (LDH) involves inflammation and metabolic stress. Tissue-specific renin-angiotensin-aldosterone system (RAAS) signaling may act as an upstream regulator of disc degeneration. This study investigates RAAS dysregulation as a central driver of LDH and its contribution to inflammation, metabolic reprogramming, and disc injury. Methods Bulk and single-cell transcriptomics assessed RAAS activity, while MR/GWAS analyses examined causality. Machine learning with the MIMIC database identified biomarkers. In vitro nucleus pulposus cell experiments validated the ACE2/Ang(1–7)/MAS1 protective axis. Results RAAS components ACE, AGTR1, ACE2, AGTR2, and MAS1 were dysregulated in LDH across disc cells, immune populations, and endothelium, with a shift toward glycolysis. Patients showed elevated Ang II/Ang(1–7) ratios. Ang II induced NF-κB mediated inflammation, extracellular matrix degradation, and apoptosis, reversible by losartan or protective axis activation. Conclusion RAAS dysregulation serves as an upstream hub driving inflammation, metabolic imbalance, extracellular matrix breakdown, and disc cell injury in LDH. Therapeutic strategies should suppress the ACE/Ang II/AT1 axis while enhancing the ACE2/Ang(1–7)/MAS1 protective pathway.