Spatial multi-omics identifies regional immunometabolic remodeling and macrophage PCK2-associated T-cell activation in lupus nephritis

Poor response of lupus nephritis (LN) to conventional therapies frequently results in persistent renal inflammation and progression of chronic renal insufficiency. The complex pathogenesis of LN, characterized by microregional immune heterogeneity and interregional crosstalk, greatly hinders identification of the core immune network initiating disease and development of effective therapeutic strategies. Given that metabolic reprogramming drives immune cell activation, exploring region-specific immunometabolic characteristics of LN kidneys is critical for clarifying disease mechanisms and therapeutic targets. This study integrated spatial proteomics, spatial metabolomics and multiplexed immunofluorescence to map the spatial immune landscape of three key regions (glomerulus, renal tubules, medulla) in LN kidneys and analyzed their distinct metabolic profiles. Significant region-specific immunometabolic dysregulation was observed. The glomerular region was enriched with neutrophils and exhibited purine metabolism disorder with upregulated ADCY4; the renal tubules showed obvious T cell aggregation and glycerophospholipid imbalance with elevated Shmt1; the medulla was characterized by macrophage accumulation and increased PCK2 expression within a pyruvate associated metabolic signature. In an inflammatory macrophage–T-cell co-culture model, PCK2 knockdown in macrophages reduced macrophage and T-cell activation readouts. This study delineates distinct region-specific immunometabolic landscapes and key regulatory molecules across different renal compartments in LN. Functional perturbation in vitro further indicated that macrophage PCK2 contributes to T-cell activation under inflammatory co-culture conditions. These findings reveal the heterogeneous immunometabolic pathogenesis of LN and provide promising region-specific metabolic targets for the precise treatment of refractory LN.