Integrated multi-omics analysis reveals AKR1C1 as a key mediator of intervertebral disc degeneration: protecting against ferroptosis via PI3K/AKT signaling.

Intervertebral disc degeneration (IDD) is a prevalent and multifactorial musculoskeletal disorder driven by complex genetic predispositions and dysregulated molecular pathways. While genetic contributions to IDD are widely recognized, the functional roles and therapeutic potential of specific causal genes remain incompletely characterized. To systematically identify novel and robust therapeutic targets, we performed an integrated multi-omics analysis. This approach integrated Mendelian randomization (MR) using large-scale GWAS summary statistics with QTL data, scRNA-seq, and bulk RNA-seq to prioritize candidate genes. Our analysis identified AKR1C1 as a candidate gene with a causal role in IDD pathogenesis. Subsequent in vitro functional studies demonstrated that elevated AKR1C1 expression activates the PI3K/AKT pathway, thereby reducing ROS accumulation and lipid peroxidation and ultimately inhibiting ferroptosis in nucleus pulposus (NP) cells. These findings indicated that AKR1C1 may be a promising therapeutic target for mitigating IDD.