Mendelian randomization analysis identifies HLA‐A and AP2M1 as genetic biomarkers linked to immune–endocytic crosstalk in intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is a major contributor to chronic spinal disorders, yet the role of endocytosis in its pathogenesis remains incompletely understood. In this study, we systematically investigated endocytosis-related genes associated with IVDD by integrating bulk transcriptome data, single-cell RNA sequencing datasets, and Mendelian randomization (MR) analysis. Differential expression analyses identified six ERGs consistently dysregulated in IVDD, among which HLA-A and AP2M1 exhibited significant causal associations with disease risk in MR analysis and were further validated in independent datasets. Functional enrichment and gene set enrichment analyses indicated that these genes were closely involved in immune-related pathways, including natural killer cell-mediated cytotoxicity and mammalian target of rapamycin signaling. Immune infiltration analysis revealed marked alterations in macrophages, activated CD4⁺ T cells, and eosinophils in IVDD tissues, with strong correlations between immune cell proportions and the expression of HLA-A and AP2M1. In vitro experiments demonstrated that overexpression of HLA-A or AP2M1 promoted nucleus pulposus cell proliferation, suppressed apoptosis, and enhanced endocytic activity, whereas in vivo overexpression alleviated disc degeneration in a rat model. Collectively, these findings identify HLA-A and AP2M1 as potential biomarkers linking immune dysregulation and endocytic dysfunction in IVDD and provide new insights into the molecular mechanisms underlying disc degeneration.