Introduction:
Osteonecrosis is a debilitating disease caused by impaired blood supply leading to bone tissue death, and drug-related osteonecrosis is a significant clinical issue.The role of inflammation and metabolic disorders in the pathogenesis of osteonecrosis has garnered widespread attention, but the exact causal relationships remain unclear.This study aims to explore the causal link between inflammatory cytokines and drug-related osteonecrosis, while also investigating how metabolites might mediate this relationship.

Material and methods:
We employed two-sample Mendelian randomization (MR) analysis to examine the causal links between 91 inflammatory cytokines, 1,400 blood metabolites, and drug-related osteonecrosis.Single nucleotide polymorphisms (SNPs) associated with inflammatory cytokines and metabolites were used as instrumental variables (IVs) to assess their potential relationship with drug-related osteonecrosis risk.We further conducted mediation MR analysis to explore the role of metabolites in mediating the impact of inflammatory cytokines on drug-related osteonecrosis.

Results:
MR analysis demonstrated notable causal relationships between four inflammatory cytokines and drug-related osteonecrosis.Specifically, Interleukin-4 (IL-4) and C-X-C motif chemokine 6 (CXCL6) showed a negative correlation with the risk of drug-related osteonecrosis, while Interleukin-6 (IL-6) and Glial cell line-derived neurotrophic factor (GDNF) exhibited a positive correlation with the risk.Furthermore, mediation analysis revealed that IL-4 affects the development of drug-related osteonecrosis via blood metabolites. Key metabolites identified as significant mediators included mannitol/sorbitol levels, the mannose-to-mannitol-to-sorbitol ratio, and the glucose-to-mannitol-to-sorbitol ratio.

Conclusions:
This study presents new evidence connecting inflammatory cytokines to drug-related osteonecrosis and highlights the mediating role of metabolites.These results help us understand the pathogenesis of the disease and provide new insights for its prevention and treatment.