Systemic lupus erythematosus (SLE) is the most common form of lupus; however, the development of new drugs for SLE has been limited, with only two drugs approved in the past 60 years. Recently, the inhibition of glycolysis and disruption of N-linked glycosylation via 2- deoxyglucose (2DG), a competitive inhibitor of glucose-6-phosphate, has shown promising results in reducing autoimmune pathology. The precise mechanism of action, however, remains unclear. To elucidate how 2DG longitudinally modulates pathways in the context of SLE, BXSB.Yaa IL15^-/-, CD8^-/- mice were treated orally with 2DG for either 96-hours or 4-weeks.

Subsequently, the transcriptional profiles of 9 tissues (heart, hippocampus, hypothalamus, kidney, liver, prefrontal cortex, skeletal muscle, small intestine, and spleen) were analyzed using unsupervised clustering and weighted gene correlation network analysis (WGCNA), ANOVA, and overrepresentation analysis. Principal component analysis showed distinct clustering based on tissue type. Through a three-step filtering procedure, we identified three response patterns to 2DG treatment: acute, long-term, or independent of dosage length. The three brain tissues had an increased immune response in both innate and adaptive immunity when treated with short-term 2DG. Five tissues, including kidney, responded to long-term 2DG treatment. Notably, 2DG predominantly affected pathways related to biosynthesis and metabolism of amino acids and genes related to glomerular nephropathy, suggesting its potential in preserving kidney function that is degraded in lupus pathogenesis. In addition, seven tissues (heart, hippocampus, hypothalamus, liver, prefrontal cortex, skeletal muscle, and spleen) were affected by 2DG regardless of dosage length. Although 2DG broadly effected pathways, each gene cluster within a tissue showed unique alterations based on time and/or treatment. Furthermore, each set of altered pathways could be classified as a downstream response to 2DG’s two major mechanisms of action: inhibition of glycolysis or disruption of N- linked glycosylation. These results show that 2DG has a systemic impact in altering immunity, amino acid metabolism, as well as other biological functions with tissue-specific variations. This study provides insights into the potential of 2DG as a therapeutic agent for addressing immune dysregulation, preserving kidney function, and treating lupus.