Immunometabolic modulators alleviate vascular dysfunction in mice with systemic lupus erythematosus Miñano, Sofía Moleón Moya, Javier González-Correa, Cristina Jiménez Moleón, Rosario Gómez-Guzmán, Manuel Martín-Morales, Natividad O´Valle, Francisco Romero Pérez, Miguel Toral, Marta Duarte Pérez, Juan Manuel Glycolysis Mitochondrial metabolism Hypertension Hypertension (HTN) is a prominent cardiovascular risk factor frequently observed in patients with systemic lupus erythematosus (SLE). This study explores whether pharmacological interventions targeting dysfunctional immune cell metabolism can confer vascular protection in a genetic mouse model of SLE. Female NZBWF1 lupus mice, aged 29 weeks, were treated for 4 weeks with either a vehicle (SLE group), a combination of 2-deoxy-Dglucose (2DG) and metformin (Met), or rapamycin. NZW/LacJ mice served as controls. The treatment with 2DG + Met inhibited splenic glycolysis and mitochondrial metabolism, enhanced AMP-activated protein kinase (AMPK) activity, and suppressed mammalian target of rapamycin (mTOR) activity. These effects resulted in a reduction in activated T helper (Th) cells and Th17 cells. The treatment managed to prevent the onset of HTN and ameliorated aortic dysfunction, as evidenced by reduced vascular contraction to the thromboxane A2 receptor agonist U46619, improved endothelium-dependent relaxation to acetylcholine, and attenuation of vascular thickening along with diminished collagen and proteoglycan accumulation. This intervention also decreased aortic Th17 cell infiltration in SLE mice, mitigating the profibrotic, proinflammatory, and oxidative stress within the vasculature, primarily via the IL-17/Rho kinase/NADPH oxidase and Rho kinase/serum response factor/myocardin pathways. Moreover, the activation of AMPK in the vascular wall by 2DG + Met improved endothelial dysfunction. Similarly, rapamycin suppressed splenic mTORC1 activity, reducing Th17 differentiation and aortic Th17 infiltration, which subsequently alleviated vascular oxidative stress and endothelial dysfunction. In conclusion, immune metabolic modulators improved vascular abnormalities in SLE mice, highlighting the potential therapeutic applications of these interventions in hypertensive SLE patients. 2025-09-18T08:49:56Z 2025-09-18T08:49:56Z 2025-11 journal article Miñano, S., Moleón, J., González-Correa, C., Jiménez, R., Gómez-Guzmán, M., Martín-Morales, N., O’Valle, F., Romero, M., Toral, M., & Duarte, J. (2025). Immunometabolic modulators alleviate vascular dysfunction in mice with systemic lupus erythematosus. Biochemical Pharmacology, 241(117154), 117154. https://doi.org/10.1016/j.bcp.2025.117154 https://hdl.handle.net/10481/106417 10.1016/j.bcp.2025.117154 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Elsevier