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Objectives Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), leading to chronic kidney damage and increased mortality. Metabolomic studies have revealed persistent mitochondrial and energy metabolism abnormalities in LN, even during remission. In LN, sodium–glucose cotransporter-2 (SGLT2) inhibition has been associated with reduced proteinuria, improved glomerular filtration rate, and attenuation of inflammatory and oxidative pathways. Experimental studies further indicate that dapagliflozin and related agents may modulate immune–metabolic axes, including IL-1 signaling, NLRP3 inflammasome activity, and mitochondrial function. This pilot study aimed to characterize plasma metabolic alterations across SLE renal phenotypes and to explore potential immunometabolic effects of dapagliflozin in lupus nephritis.Methods Thirty-six female SLE patients were stratified into four subgroups: active LN (n=8), inactive LN without SGLT2 inhibitor therapy (n=10), inactive LN treated with dapagliflozin (n=10), and inactive non-LN SLE (n=8). All LN cases were biopsy-proven ISN/RPS class III, IV, or pure class V nephritis. Fasting plasma samples were analyzed using untargeted gas chromatography–mass spectrometry (GC–MS). Data were normalized by log-transformation and Pareto scaling. Principal component analysis (PCA) and pathway enrichment analysis (MetaboAnalyst 5.0, KEGG database) were used to identify distinct metabolic signatures among groups.Results Inactive LN patients demonstrated differential regulation of tricarboxylic acid (TCA) cycle intermediates, fatty-acid β-oxidation, and branched-chain amino acids (p<0.05) compared with inactive non-LN SLE, indicating persistent mitochondrial and redox dysregulation despite clinical remission. Dapagliflozin-treated LN patients exhibited a unique serine-centered metabolic signature involving ABC transporter and cofactor biosynthesis pathways, suggesting systemic metabolic reprogramming associated with SGLT2 inhibition. These alterations align with experimental findings that SGLT2 blockade modulates IL-1 signaling, NLRP3 inflammasome activity, and mTOR-driven metabolic stress. No major differences were detected between active and inactive LN subgroups after multiple-testing correction.Abstract PT2:02 Figure 1PCA score plot demonstrating partial separation between inactive LN and inactive non-LN groups, with enrichment in TCA cycle, fatty-acid β-oxidation, and branched-chain amino acid metabolism (p<0.05)Conclusions This pilot metabolomic study provides novel insights into systemic metabolic remodeling in lupus nephritis and identifies dapagliflozin-associated shifts in amino acid and energy metabolism. The serine-centered signature observed in SGLT2 inhibitor–treated patients suggests potential pharmacometabolic modulation beyond glycemic control. These findings support further longitudinal and mechanistic studies to clarify how SGLT2 inhibition may restore immunometabolic balance and enhance renal resilience in SLE.