Mendelian randomization and drug repurposing analysis identifies APOE as a potential therapeutic target for low back pain

Abstract

Abstract Background: Low back pain (LBP) is a prevalent chronic pain syndrome primarily driven by spinal degeneration, causing persistent disability and reduced quality of life. Despite available interventions, identifying novel therapeutic targets remains imperative for modifying disease progression. Methods: We performed Mendelian randomization (MR) analyses integrating plasma proteomics data (4,657 proteins in 7,213 Europeans) and FinnGen R12 LBP GWAS (17,615 cases/420,066 controls). Robustness was confirmed via Bayesian colocalization and Steiger directionality tests. Protein-protein interaction (PPI) networks, functional enrichment (KEGG/GO), single-cell annotation, and druggability assessments were subsequently applied. Results: MR identified APOE as causally protective against LBP (OR = 0.86, 95% CI: 0.81–0.91, P = 5.12×10⁻⁷). Bayesian colocalization supported shared causal variants, while Steiger test excluded reverse causation. PPI networks revealed interactions between APOE and established LBP drug targets. Functional analyses demonstrated APOE's enrichment in lipid metabolism pathways (particularly cholesterol transport), with elevated expression in macrophages/fibroblasts and hepatic/cerebral tissues. Druggability assessment indicated:Glucocorticoids directly upregulate endogenous APOE;Inflammatory cytokine receptor antagonists and PPARγ agonists indirectly enhance APOE activity. Conclusion: Genetically elevated APOE expression reduces LBP risk, establishing its therapeutic potential. Pharmacological modulation of APOE—via glucocorticoids, cytokine antagonists, or PPARγ agonists—represents a novel strategy for early intervention in disc degeneration.