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

## TL;DR

This study uses multi-omics methods to identify ACOX2 as a protective gene in IgA nephropathy, linked to cholesterol metabolism and a potential drug target.

## Contribution

ACOX2 is newly identified as a protective biomarker and therapeutic target in IgA nephropathy through a multi-omics approach.

## Key findings

- ACOX2 expression is inversely associated with IgA nephropathy risk (OR = 0.917, 95% CI: 0.879–0.957).
- ACOX2 is downregulated in proximal tubular cells of IgA nephropathy patients.
- Flavin adenine dinucleotide (FAD) shows strong binding to ACOX2 and may be a therapeutic compound.

## Abstract

The role of cholesterol metabolism in IgA nephropathy (IgAN) remains poorly understood.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s41065-026-00639-0.

This study investigates the role of cholesterol metabolism in the pathogenesis of IgA nephropathy (IgAN) using a multi-omics approach.ACOX2 was identified as a key hub gene in IgAN, with lower expression in proximal tubular cells of patients with IgAN.Mendelian randomization (MR) and colocalization analyses show a significant negative association between ACOX2 expression and IgAN risk.Flavin adenine dinucleotide (FAD) was identified as a potential therapeutic compound for IgAN, showing strong binding to ACOX2.ACOX2 may serve as a potential biomarker and therapeutic target for IgAN

This study investigates the role of cholesterol metabolism in the pathogenesis of IgA nephropathy (IgAN) using a multi-omics approach.

ACOX2 was identified as a key hub gene in IgAN, with lower expression in proximal tubular cells of patients with IgAN.

Mendelian randomization (MR) and colocalization analyses show a significant negative association between ACOX2 expression and IgAN risk.

Flavin adenine dinucleotide (FAD) was identified as a potential therapeutic compound for IgAN, showing strong binding to ACOX2.

ACOX2 may serve as a potential biomarker and therapeutic target for IgAN

The online version contains supplementary material available at 10.1186/s41065-026-00639-0.