YTHDF3-associated m6A regulation and cuproptosis-related gene expression in steroid-induced osteonecrosis of the femoral head.

This study aims to explore the role of N6-methyladenosine (m6A) RNA modification in regulating Cuproptosis in steroid-induced osteonecrosis of the femoral head (SONFH), providing insights into its underlying mechanisms and therapeutic targets. Gene expression profiles from both human (GSE123568; 30 SONFH patients and 10 controls) and rat femoral head samples (GSE26316; 3 SONFH and 3 controls) were analyzed to identify differentially expressed genes (DEGs) and enriched pathways. In a matched case-control study, femoral head tissues from SONFH patients and non-SONFH controls were collected. The expression of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) and dihydrolipoamide dehydrogenase (DLD) was measured using qRT-PCR and Western blotting. Functional validation was performed in human bone marrow mesenchymal stem cells (BMSCs) via siRNA-mediated knockdown of YTHDF3 and treatment with elesclomol, a cuproptosis inducer. In the GSE26316 and GSE123568 datasets, we identified 708 common DEGs. Cuproptosis were activated in SONFH. The expression levels of YTHDF3 and DLD were elevated in SONFH tissues. Knockdown of YTHDF3 reduced the DLD expression and mitigated the inhibitory effects of elesclomol on BMSC proliferation and osteogenesis. YTHDF3 may contribute to SONFH progression by regulating DLD expression and cuproptosis, offering a potential important molecular target for novel therapeutic strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10735-025-10544-x.