Targeting TKT-associated immunometabolic remodeling attenuates experimental lupus nephritis and NET-related...

Lactic acid metabolism and neutrophil extracellular traps (NETs) are critical immune regulators, yet their specific crosstalk in systemic lupus erythematosus (SLE) and lupus nephritis (LN) pathogenesis remains poorly understood. Here, by integrating bulk and single-cell RNA sequencing (scRNA-seq) analyses, we identified TKT and ITGAM as pivotal upregulated genes in SLE, demonstrating robust diagnostic value (AUC >0.7) supported by reliable nomogram models. Additional analysis of a human LN renal biopsy dataset (GSE32591) showed increased ITGAM and TKT in LN glomerular samples, supporting their renal relevance. Regulatory network analyses suggested potential molecular interactions involving these genes with specific microRNAs (e.g., hsa-miR-142-5p-ITGAM and hsa-miR-1-3p-TKT), while scRNA-seq analysis suggested cell-type-associated expression patterns, with donor-level analysis showing higher TKT expression in monocytes from SLE patients. To translate these computational insights into biological relevance, we conducted rigorous in vivo validations. In an apoptotic cell-induced LN mouse model, we confirmed renal injury, increased ITGAM and TKT protein expression, and enrichment of TKT in CD14⁺ monocyte-lineage cells. Crucially, targeted pharmacological inhibition of TKT using oxythiamine significantly mitigated disease progression in LN mice. Oxythiamine treatment not only restored renal function and attenuated tissue fibrosis but also reprogrammed aberrant lipid metabolism and cellular proliferation. Oxythiamine treatment was further associated with reduced ITGAM expression and lower renal Cit-H3 levels, consistent with an attenuation of NET-associated inflammatory activity. Together, our integrated multi-omics and in vivo data indicate that TKT is closely linked to immunometabolic remodeling in experimental lupus nephritis, accompanied by alterations in lactate accumulation, ITGAM expression, and NET-associated inflammatory activity. These findings support TKT-associated metabolic remodeling as a potential therapeutic avenue that warrants further mechanistic investigation in LN.