PT1:07 Functional iron deficiency drives metabolic reprogramming in classical monocytes derived from patients with systemic lupus erythematosus

Objectives Defective clearance of apoptotic material through innate immune dysregulation contributes to SLE. Iron is essential for monocyte mitochondrial oxidative phosphorylation (OXPHOS) via iron–sulfur complexes. In inflammation, hepcidin (induced by IL-6/IL-1b) degrades ferroportin (FPN1) to restrict iron export, while cells upregulate transferrin receptor (TfR) resulting in functional iron deficiency (FID), which may promote mitochondrial dysfunction and ROS. We explored whether FID is present in SLE and how it impacts monocyte mitochondrial-metabolism.Methods Serum iron-handling mediators were quantified by ELISA in SLE (n=39) and healthy controls (HC, n=33) and visualised by heatmap with K-means clustering. Peripheral blood monocytes were profiled by flow cytometry for subsets (classical CD14+, intermediate CD14+CD16+, non-classical CD16+), TfR, mitochondrial mass, and mito-ROS. Classical monocytes were isolated for immunoblotting of FPN1 and respiratory chain complexes I–V. Cellular iron deficiency was modelled in healthy monocytes with deferiprone 500 µM. Mitochondrial respiration (basal/maximal OXPHOS) was measured by Seahorse XF Mito Stress Test under iron-deficient vs replete conditions and ex vivo in HC (n=15) vs SLE (n=25) classical monocytes. Active SLE was defined by BILAG 1A/2B.Results Serum iron mediators segregated SLE into low vs high-activity clusters ( figure 1A; median Global BILAG 0 vs 13, p