New evidence for the protective effect of gut microbiota regulation of ferroptosis-related proteins against osteoporosis.

Osteoporosis (OP), characterized by bone degradation and increased fracture susceptibility, constitutes a significant global health burden. Recent findings implicate gut microbiota and ferroptosis in the regulation of bone metabolism; however, causal evidence for the gut microbiota's influence on OP specifically via ferroptosis regulation remains to be established. This study employed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics to investigate these causal relationships and delineate mediating pathways.We assessed causal links between gut microbiota, ferroptosis-related proteins, and OP risk. Associations for gut microbiota abundance and ferroptosis-related proteins were derived from GWAS data and Icelandic blood-derived protein quantitative trait loci, respectively. Outcome data for OP were obtained from the FinnGen Release R12. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy.  MR analysis identified 33 gut microbial taxa causally associated with OP risk: 13 protective and 20 detrimental. Similarly, 34 ferroptosis-related proteins were categorized as protective (18) or detrimental (16) for OP. Mediation analysis revealed that the protective effect of Terrisporobacter othiniensis on OP is partially mediated by the ferroptosis regulator MDM4 (indirect effect β = -0.020, 95% CI: -0.068 to 0.029), accounting for 6.8% of the total effect. Sensitivity analyses showed no significant evidence of heterogeneity or horizontal pleiotropy. This study provides the first genetically validated evidence supporting a causal relationship between specific gut microbiota, ferroptosis-associated proteins, and OP susceptibility. Specifically, Terrisporobacter othiniensis demonstrates a novel protective mechanism, modulating OP risk partly through the ferroptosis regulator MDM4. These findings broaden understanding of the "gut-bone axis" and highlight the gut microbiota-ferroptosis pathway, particularly the MDM4/p53 axis, as a promising target for novel OP prevention and therapeutic strategies.