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Background <p>The role of cholesterol metabolism in IgA nephropathy (IgAN) remains poorly understood.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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  • Xiaoqi Deng,
  • Jinlan Wu,
  • Mengxi He,
  • Lin Mei,
  • Li Ma,
  • Yun Lin,
  • Yu Luo

摘要

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.