Table 1.
Novel therapeutic strategies that target immunometabolism in SLE.
| Biological process targeted | Targeted molecule | Drug | Model | Proposed mechanism in SLE | Reference |
|---|---|---|---|---|---|
| Mitochondrial dysfunction and oxidative stress | mROS | Idebenone | MRL-lpr, NZM2328 | • Mitochondrial metabolism and mROS-NETosis modulation. | Blanco et al.(43) |
| MitoQ | MRL-lpr | • Mitochondrial metabolism and mROS-NETosis modulation. • Reduced MAVS oligomerization and IFN-α. |
Fortner et al.(13) | ||
| HRES-1/Rab4 and Rab5 | 3-PEHPC | MRL-lpr | • Downregulation of IL-10. • Reversal of Drp1 protein depletion; reduction of mitochondrial mass in T and B cells and macrophages. |
Caza et al.(47) | |
| VDAC1 | VBIT-4 | MpJ-Faslpr | • Decreased cell-free mtDNA and ISG expression. • mROS-NETosis modulation. |
Kim et al.(34) | |
| mTOR pathway | mTORC1 | Rapamycin (sirolimus) | MRL-lpr, NZB/W F1, Srsf1-cKO mice, human SLE | • Downregulation of proinflammatory cytokines. • Decreased Tfh cell infiltration. • Restoring Th17/Treg balance and increasing CD8+ memory T cells. • Targeting cGAS-STING pathway and ISG expression in myeloid cells. |
Katsuyama et al.(15) Zhang et al.(51) Eriksson et al.(50) Zhao et al.(52) Yap et al.(53) Murayama et al.(24) |
| GSH | NAC | NZB × NZW F1, human SLE | • Increased GSH levels in PBLs and reversed mTOR activity. • Enhanced mitochondrial mass and hyperpolarization, and apoptosis of CD4−CD8−TCR-αβ+ T cells. • Increased Treg cells count. |
Lai et al.(54) | |
| mTORC1/2 | INK-128 | MRL/lpr, Pristane-induced lupus mice | • Impairing CD11b+Gr1+ cell differentiation. | Shi et al.(25) | |
| AMPK, ETC | Metformin | B6.Sle1.Sle2.Sle3, NZB/W mice, Roquinsan/san mice, human SLE | • Synergistic effect with 2-DG to reduce glycolysis and OXPHOS, and IFN-γ production. • Restored IL-2 production and decreased ISGs expression in CD4+ T cells. • Reduced GC B cells and autoantibodies production. • Restoring Th17/Treg cells balance. |
Yin et al.(44) Titov et al.(14) Lee et al.(45) | |
| Glycolysis | CAMK4 | KN-93 | MRL-lpr, human SLE | • Restoring Th17/Treg cells balance. • Decreased glycolysis-related proteins expression in T cells under Th17-polarizing conditions. • mTOR pathway downregulation. |
Koga et al.(30, 55) |
| Glucose transporters | CG-5 | B6.NZM2410.Sle1.Sle2.Sle3, human SLE | • Decreased glycolysis-related proteins expression and increased FAO and PPP in activated CD4+ T cells. • Restoring Th17/Treg cells balance. • Reduced GC B cells and autoantibodies production. |
Li et al.(56) | |
| Glutaminolysis | Gs1 | BPTES | MRL-lpr, human SLE | • Decreased CD4−CD8−TCR-αβ+ T cells counts and Th17 differentiation. • Decreased glycolysis favored by reduced HIF-α levels. |
Kono et al.(27) |
| Lipids metabolism | HMG-CoA reductase | Statins | gld.apoE−/− mice, NZB/W F1, human SLE | • Downregulation of proinflammatory cytokines, TLR2 and MHC-II expression. • Cholesterol and lipid metabolism, oxidative stress and mitochondrial activity modulation in monocytes. |
Tan et al.(57) Ruiz-Limón et al.(58) |
| GlcCer synthase | Genz-667161 | MRL-lpr | • Reduction of GSL hexosylceramide and ganglioside GM3 levels. | Nowling et al.(37) |
2-DG = 2-deoxyglucose; AMPK = AMP-activated protein kinase; CaMK4 = calcium/calmodulin-dependent protein kinase 4; cGAS-STING = cyclic guanosine monophosphate-–adenosine monophosphate synthase (cGAS)-Stimulator of Interferon Genes (STING); Drp1 = dynamin-related protein 1; ETC = electron transport chain; FAO = fatty acid oxidation; GC = germinal center; GlcCer synthase = UDP-glucose:ceramide glucosyltransferase; Gls1 = glutaminase 1; GSH = glutathione; GSL = glycosphingolipids; HIF-1α = hypoxia-inducible factor 1α; HMG-CoA = 3-hydroxy-3-methyl-glutaryl-coenzyme A; ISGs = type I interferon (IFN)-stimulated genes; MAVS = mitochondrial antiviral stimulator; MHC-II = major histocompatibility complex class-II; mROS = mitochondrial reactive oxygen species (ROS); mtDNA = mitochondrial DNA; mTOR = mammalian target of rapamycin; mTORC1 = mTOR complex 1; mTORC1/2 = mTOR complex 1 and 2; NAC = N-acetylcysteine; OXPHOS = oxidative phosphorylation; PBLs = peripheral blood lymphocytes; PPP = pentose phosphate pathway; SLE = systemic lupus erythematosus; SRSF1 = serine/arginine-rich splicing factor 1; VDAC1 = voltage-dependent anion channel 1.