Unveiling cholesterol metabolism-related gene ACOX2: a multi-omics discovery of a novel biomarker in IgA nephropathy

BACKGROUND: The role of cholesterol metabolism in IgA nephropathy (IgAN) remains poorly understood. METHODS: We applied a multi-omics integrative framework to systematically identify key regulatory genes. This approach combined genome-wide association study (GWAS), summary-data-based mendelian randomization (SMR), conventional MR, Bayesian colocalization, single-cell RNA sequencing (scRNA-seq), bulk transcriptome validation, molecular docking, and molecular dynamics simulations. RESULTS: ACOX2 was identified as a protective hub gene. Genetic analyses revealed an inverse association between ACOX2 expression and IgAN risk (OR = 0.917, 95% CI: 0.879-0.957; PPH4 = 90.75%). scRNA-seq demonstrated the downregulation of ACOX2 in proximal tubular cells, which was further confirmed in external datasets. Molecular docking and molecular dynamics simulation suggested flavin adenine dinucleotide (FAD) as a potential therapeutic ligand targeting ACOX2. CONCLUSION: This study uncovers a cholesterol metabolism-related regulatory axis in IgAN, establishes ACOX2 as a protective biomarker, and highlights a therapeutically actionable pathway; it provides mechanistic insights and translational opportunities for biomarker development and drug discovery.