Bilirubin reductase regulates macrophage senescence and modulates implant-associated Staphylococcus aureus osteomyelitis.

PURPOSE: Osteomyelitis (OM) remains difficult to diagnose early due to its heterogeneous pathology and reliance on invasive biopsy. This study aimed to identify reliable diagnostic biomarkers and explore their roles in macrophage senescence during OM pathogenesis.

METHODS

We integrated single-cell RNA sequencing, bulk transcriptomics, and senescence-related gene sets to identify key genes. A diagnostic model was constructed using 3 machine-learning algorithms. Mendelian randomization analysis was applied to infer causality. Biliverdin Reductase A (BLVRA)'s role in macrophage senescence was validated through in vitro and in vivo Staphylococcus aureus infection models.

RESULTS

Seven diagnostic biomarkers were identified, with a combined model showing high accuracy (area under the curve? > 0.96). Mendelian randomization analysis confirmed a causal effect of BLVRA on OM risk. Single-cell data revealed predominant BLVRA expression in macrophages. Experimental validation showed that Staphylococcus aureus infection upregulates BLVRA and promotes macrophage senescence.

CONCLUSION

BLVRA is a causal mediator of OM linked to macrophage senescence. This multi-omics approach offers a basis for early diagnosis and suggests potential immunotherapeutic targets for OM.