Integrated Multiomics Analysis Identifies CDO1 as a Novel Therapeutic Target for Osteoarthritis.

Abstract

Introduction: This study aimed to identify key genes and potential therapeutic targets involved in the progression of osteoarthritis (OA) through an integrated multi-omics approach.

Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis on OA and control samples to define cell types and differentially expressed genes (DEGs). Bulk RNA-seq data from 7 public OA datasets were analyzed to identify DEGs, and Weighted Gene Co-expression Network Analysis (WGCNA) identified key co-expressed modules. An Integrated analysis of scRNA- seq DEGs, bulk RNA-seq DEGs, and WGCNA module genes pinpointed overlapping candidates. Functional enrichment analysis of these genes was then conducted. Mendelian randomization (MR) analysis was used to assess causal relationships between candidate genes and OA risk. The top candidate gene, CDO1, was functionally validated using siRNA-mediated knockdown in a rat OA model, assessed by histology and immunohistochemistry.

Results: scRNA-seq identified 11 distinct cell types and 4,316 DEGs. Bulk RNA-seq meta-analysis revealed 3,664 DEGs, with WGCNA highlighting a key module significantly associated with OA. Integration identified 932 overlapping DEGs. Enrichment analysis implicated pathways including ferroptosis, PI3K-Akt signaling, and ECM-receptor interaction. MR analysis established CDO1 as the top causal OA risk gene (OR [95% CI] = 0.998 [0.996-0.999], P = 0.003).

Discussion: In vivo, CDO1 knockdown significantly delayed OA progression in rats. Compared to controls, the si-CDO1 group showed improved cartilage structure, increased chondrocyte numbers, and enhanced type II collagen expression.

Conclusion: CDO1 is a novel OA risk gene and therapeutic target. Its inhibition protects against OA progression, as supported by integrated multi-omics analysis and in vivo validation.