Glucose-Derived Carbon Nanoparticles/Manganese (GCNPs/Mn) Ameliorate Experimental Myeloperoxidase (MPO)-ANCA-Associated Vasculitis by Attenuating Ferroptosis Through Enhancing Manganese Superoxide Dismutase (MnSOD) Activity

Background: This study clarifies NETs-induced endothelial injury mechanisms and investigates GCNPs/Mn for ANCA-associated vasculitis (AAV) treatment. Methods: We measured markers (oxidative stress, ferroptosis proteins etc.) to clarify ferroptosis in NETs-induced endothelial injury and GCNPs/Mn's effects. RNA sequencing and MnSOD siRNA explored its mechanism. In vivo, AAV models were established in WKY rats via MPO or PTU to evaluate the renal injury. Results: In vitro tests showed NETs caused endothelial injury, mitochondrial dysfunction, oxidative stress, and ferroptosis-related changes (Fig 1A-E). GCNPs/Mn inhibited NETs-induced ferroptosis and injury (Fig 1F), restoring MnSOD activity (Fig 1G). Confocal and ICP-MS revealed GCNPs/Mn released Mn ions in lysosomes (Fig 1H). MnSOD siRNA blocked GCNPs/Mns protective effects (Fig 1I-J). Transcriptomics linked its action to NF-κB (Fig 1K), confirmed by protein assays (Fig 1L-M). In animal models, GCNPs/Mn reduced renal ferroptosis, injury, and proteinuria, restoring function (Fig 2). Conclusion: GCNPs/Mn alleviates endothelial cell injury related to ferroptosis induced by NETs by regulating the MnSOD/NF-κB signaling pathway, providing new insights into AAV pathogenesis and potential therapeutic strategies.