Zingerone treats postmenopausal osteoporosis via increased ferroptosis sensitivity by p53-mediated regulation of Sat1 and Gpx4 expression

Zingerone, a component of dried ginger, has known anti-ulcer and bone growth-promoting effects, but its impact on postmenopausal osteoporosis (PO) is unclear. This study investigates the therapeutic potential and underlying mechanisms of zingerone in PO. A concentration-dependent effect identified on osteoclast precursors: at low concentrations, zingerone maintains low ROS levels, enhance proliferation, and facilitates bone remodelling; at high concentrations, it elevates ROS levels, enhances ferroptosis sensitivity, and suppresses osteoclast formation. Zingerone significantly improves bone mass in an ovariectomised mouse model of PO. Metabolomics identifies 869 differential metabolites linked to glutathione and purine metabolism. Transcriptomics highlights pathways including ferroptosis, leukocyte migration, and cell adhesion. In RAW264.7 cells, zingerone modulates p53, enhances ferroptosis sensitivity, increasing ROS and Fe2+, upregulates Sat1, and downregulates Gpx4, suggesting that zingerone may act via p53-mediated ferroptosis, indicating potential clinical utility. Before clinical application, the dose-dependent effects of zingerone on bone remodelling and its underlying mechanisms warrant further investigation. Overall design: Novogene Co., Ltd. in Beijing, China conducted RNA sequencing analysis on three replicates of mouse femoral tissue. Differential expression analysis was carried out using the DESeq2 R package for two groups, each with three biological replicates. Differential gene analysis was done using the Limma package in R, with a cut-off threshold of abs(log2) > 0.2. Genes with a p value < 0.05 were deemed significantly differentially expressed. Significantly enriched genes among the DEGs were identified based on corrected p values below 0.05. Statistical enrichment of annotated genes was performed using the KEGG pathway database and the clusterProfiler R package. Additionally, Gene Set Enrichment Analysis (GSEA) was conducted utilizing the clusterProfiler R package. Multiplicative changes in gene expression were calculated for group comparisons, leading to the generation of gene lists based on |log2FC| changes. Pearson correlation analysis was undertaken to assess the correlation between genes and metabolites, with statistical significance set at a p value of less than 0.05.