Decreased serum and local GPX4 and SLC7A11 expression correlates with disease severity in non-traumatic osteonecrosis of the femoral head.

BACKGROUND: Ferroptosis is implicated in various musculoskeletal conditions, including non-traumatic osteonecrosis of the femoral head (NT-ONFH). OBJECTIVE: The objective of this study was to explore the levels of two crucial proteins associated with ferroptosis, namely Glutathione peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), in both serum and femoral head samples, and to correlate their expression levels with the clinical severity of NT-ONFH. METHODS: The study included 136 NT-ONFH patients and an equal number of healthy controls. In addition, 68 subjects suffering from femoral neck fractures (FNF) were included in the study. The serum concentrations of GPX4 and SLC7A11 were quantified using the enzyme-linked immunosorbent assay. The GPX4 and SLC7A11 levels among tissue samples were identified through immunohistochemical staining, western blot analysis, and quantitative real-time polymerase chain reaction (qRT-PCR). The radiographic severity of the condition was evaluated utilizing the Association Research Circulation Osseous (ARCO) classification system, while the symptomatic severity was assessed utilizing the Visual Analogue Scale (VAS) alongside the Harris Hip Score (HHS). RESULTS: Patients diagnosed with NT-ONFH had considerably reduced serum concentrations of GPX4 and SLC7A11 in comparison to individuals in the healthy control group. Negative correlations of serum GPX4 and SLC7A11 levels with the ARCO stages were observed. A total of 73 ONFH and 68 FNF patients underwent total hip replacement. The mRNA and protein levels of GPX4 and SLC7A11 were lower in the necrotic areas compared to the non-necrotic areas and FNF femoral head tissues. Subsequent Receiver operating characteristic (ROC) curve analysis suggested that the decreased levels of both serum and local GPX4 and SLC7A11 could serve as potential biomarkers for the progression of ONFH. Furthermore, serum and local GPX4 and SLC7A11 levels were found to be negatively linked to the VAS score but positively related to the HHS score. CONCLUSION: The levels of GPX4 and SLC7A11, both in serum and at the local site, were inversely correlated with the progression of NT-ONFH. Targeting ferroptosis and its associated proteins through potential therapeutic interventions could be a viable strategy to mitigate the severity of NT-ONFH.