Allogeneic mesenchymal stromal cells ameliorate lupus nephritis by regulating lipid metabolism via ASGR1

Systemic lupus erythematosus (SLE) is an autoimmune disease in which disruptions in lipid metabolism contribute to immune dysregulation, inflammation, and organ damage. This study aims to elucidate the role of hepatic asialoglycoprotein receptor 1 (ASGR1) in lipid metabolism dysregulation in lupus nephritis, and to investigate the therapeutic potential of mesenchymal stromal cells (MSCs) in restoring lipid homeostasis via ASGR1 modulation. A high-fat diet (HFD)-fed MRL/ lpr lupus mouse model was used to assess the impact of lipid dysregulation on lupus pathology. ASGR1 expression and cholesterol metabolism-related genes were evaluated using molecular and histological analyses. Liver-specific Asgr1 knockdown was achieved using adeno-associated virus. The therapeutic effects of MSCs were evaluated both in vivo and in vitro, with a focus on ASGR1 regulation and downstream metabolic signaling. In MRL/ lpr mice, HFD exacerbated lipid accumulation, renal injury, and immune imbalance. ASGR1 expression was significantly upregulated in the liver, leading to suppressed cholesterol efflux and enhanced lipid synthesis. Asgr1 knockdown ameliorated these metabolic disturbances. MSCs treatment reduced ASGR1 expression, restored lipid homeostasis, and improved lupus phenotypes by modulating mTOR, LXRα, and AMPK pathways. Overexpression of Asgr1 reversed the protective effects of MSCs in vitro. Lipid metabolism dysregulation contributes to SLE pathogenesis through ASGR1-mediated pathways. Targeting ASGR1, particularly via MSCs therapy, offers a promising strategy to restore metabolic balance and attenuate disease severity in lupus nephritis.