Placental alkaline phosphatase promotes lipid accumulation and fibrosis in ligamentum flavum hypertrophy and represents a potential target for statin repurposing

Background and objective Lumbar spinal stenosis is a prevalent degenerative disorder driven primarily by ligamentum flavum hypertrophy. Emerging evidence links ectopic lipid accumulation to fibrotic remodeling and suggests a potential contribution of immune dysregulation. However, the molecular targets connecting lipid accumulation with ligamentum flavum fibrosis remain incompletely defined. We sought to evaluate the underlying mechanisms of lipid-lowering drug targets in lipid-associated ligamentum flavum fibrosis. Methods We applied two-sample Mendelian randomization (MR), summary-data-based MR, and Bayesian colocalization to evaluate the associations of genetically proxied levels of 213 lipid-lowering drug target proteins with lumbar spinal stenosis risk. Candidate targets were evaluated via genetic immune-cell mediation analysis, molecular docking, molecular dynamics simulations, and experimental validation in vitro and in vivo . Results MR identified three proteins increasing disease risk, with placental alkaline phosphatase (ALPP) consistently replicating across platforms (colocalization at rs12478529, PP.H4 = 0.9979). Genetically inferred mediation analysis suggested that selected immune-cell traits may partially mediate the association between ALPP and lumbar spinal stenosis. Molecular dynamics simulations and cellular thermal shift assays supported target engagement of atorvastatin and simvastatin with ALPP. In clinical specimens, ALPP was upregulated in hypertrophied tissues, co-localizing with fibrosis and lipid accumulation. In vitro , statins suppressed lipid accumulation and fibrotic markers; ALPP overexpression counteracted these protective effects. In vivo , systemic statin administration attenuated ligamentum flavum thickening, whereas local viral-mediated ALPP overexpression reversed this benefit. Conclusion Our findings identify ALPP as a genetically supported candidate associated with LSS and link it to lipid accumulation and fibrosis. Computational and CETSA findings support possible target engagement of statins with ALPP and attenuate lipid accumulation and fibrosis, supporting ALPP as a potential mediator of their effects and statin repurposing for LSS.