GLP-1 receptor agonists as novel renoprotective agents in lupus nephritis

Abstract Background Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus and a major cause of chronic kidney disease (CKD). Despite advances with immunosuppressive therapy, many patients continue to develop progressive renal impairment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), approved for diabetes and CKD, have shown renoprotective effects, but their potential in LN remains undefined. Methods We evaluated the renoprotective effects of liraglutide in lupus-prone MRL/lpr mice using functional, histopathological, and molecular analyses integrated with single-nucleus transcriptomics. Mechanistic studies involved ferroptosis inhibition and pharmacological blockade of cAMP signaling. To provide clinical context, we also describe a patient with class III + V LN who initiated semaglutide during immunosuppressant tapering. Results In lupus-prone MRL/lpr mice, liraglutide reduced proteinuria, improved renal function, and ameliorated histopathological injury without altering systemic autoantibody levels. Single-nucleus transcriptomics revealed cell type–specific remodeling, including suppression of inflammatory and metabolic pathways in podocytes, mesangial, and tubular cells, alongside signatures of tubular repair. Liraglutide treatment was associated with reduced immune infiltration, NF-κB and NLRP3 signaling, fibrosis, oxidative stress, and ferroptosis-related changes, as well as enhanced autophagy. Ferroptosis inhibition recapitulated several protective effects of liraglutide, whereas cAMP blockade attenuated its effects on renal function, inflammation, oxidative stress, and ferroptosis-related parameters. In a single clinical observation, proteinuria decreased following semaglutide initiation during ongoing immunosuppressive management; however, no causal inference can be made from this case. Conclusions GLP-1RAs improved renal outcomes in lupus-prone mice in association with anti-inflammatory, antioxidant, and reduced ferroptosis-related changes. Pharmacological experiments further support the involvement of cAMP signaling and ferroptosis in these renoprotective effects.