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Objectives Methylprednisolone (mPSL) pulse therapy is an essential treatment for systemic lupus erythematosus (SLE); however, it carries a risk of osteonecrosis of the femoral head (ONFH). While the underlying mechanisms of this complication are poorly understood, our preceding studies suggest that hyperlipidemia promotes microcirculation disorders in lupus mice by driving neutrophil extracellular trap (NET) formation. This NET formation is mechanistically linked to prenylcysteine oxidase 1 (PCYOX1), an enzyme involved abundantly in very low-density lipoproteins (VLDL), which produces the NET-inducers hydrogen peroxide and farnesal. Thus, we hypothesized that elevated VLDL levels may predispose patients with SLE to ONFH after mPSL pulse therapy. To verify the hypothesis, histopathological examinations were conducted to demonstrate that ONFH was developed specifically in hyperlipidemic lupus mice following mPSL pulse.Methods SLE was induced using the TLR7 agonist imiquimod (IMQ) in C.KOR/StmSlc-Apoeshl (Apo E mutant) mice, which spontaneously develop hyperlipidemia, and in normal BALB/c mice. C.KOR/StmSlc-Apoeshl and BALB/c mice without lupus induction served as controls. All groups received mPSL pulse or PBS injection as controls. At sacrifice, whole blood was collected to analyze plasma lipid profiles by HPLC and to measure PCYOX1 concentrations by ELISA. Post-mortem histopathological assessment was performed. ONFH was evaluated by H&E staining and infiltration of NET-forming neutrophils were detected by immunofluorescent staining for NETs.Results Elevated total cholesterol and triglycerides, primarily concentrated in the VLDL fraction, were observed only in the IMQ-plus-mPSL-treated C.KOR/StmSlc-Apoeshl mice, whereas plasma levels of PCYOX1 were elevated in both IMQ-plus-mPSL-treated BALB/c and C.KOR/StmSlc-Apoeshl mice. Femoral head osteocyte necrosis and mild bone marrow necrosis were observed in IMQ-plus-mPSL-treated C.KOR/StmSlc-Apoeshl mice, but not in other groups. Accumulation of NET-forming neutrophils were evident in vessels surrounding the necrotic femoral head.Abstract PT6:04 Figure 1Conclusions mPSL pulse in lupus mice with hyperlipidemia induced ONFH. Promoted NET formation may be involved in the development of ONFH. Although further studies are needed, this study suggests that hyperlipidemia can be a risk factor for the development of ONFH following mPSL pulse therapy in patients with SLE.