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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<0.0001). Compared with HC, SLE showed reduced transferrin (p=0.03) and elevated hepcidin (p=0.001) with associated increased IL-6/IL-1B (p<0.0001) consistent with inflammatory iron sequestration. A cell-intrinsic FID phenotype was evident with increased TfR on classical (p=0.016) and intermediate (p=0.046) monocytes (figure 1B). Decreased FPN1 was observed in SLE monocytes (p=0.031, figure 1C) aligned with impaired iron export. In healthy monocytes, iron chelation reduced basal (p=0.001, figure 1D) and maximal OXPHOS (p<0.0001, figure 1E), linking iron availability to respiration. SLE classical monocytes mirrored this with reduced basal (p=0.004, figure 1F) and maximal OXPHOS (p=0.002, figure 1G) vs HC, alongside increased mitochondrial mass (p=0.030, figure 1H) and ROS generation (p=0.044; mass-adjusted p=0.040, figure 1I–J), indicating compensatory biogenesis with oxidative stress. Iron dependent Complex I abundance was lower in classical SLE monocytes (p=0.009, figure 1K).Abstract PT1:07 Figure 1(A) Serum iron mediators segregated SLE based on disease activity defined by BILAG. (B) Cell-intrinsic functional iron deficiency is observed with increased cell surface TfR on classical and intermediate monocytes observed (C) Monocyte FPN1 expression was found to be reduced in SLE (D–E) In healthy monocytes, iron chelation reduced basal OXPHOS and maximal OXPHOS. (F–G) Classical SLE monocytes showed analogous reduced basal and maximal OXPHOS vs HC. (H–J) SLE monocytes show increased mitochondrial mass and ROS generation. (K) Iron dependent mitochondrial Complex I abundance was lower in SLE CD14+ monocytes compared with HCConclusions Systemic and cellular readouts converge on FID-driven mitochondrial reprogramming and bioenergetic impairment in SLE classical monocytes, with increased mitochondrial mass but reduced respiratory capacity and heightened oxidative stress.