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Renal ischemia-reperfusion injury (IRI) poses a significant challenge in kidney transplantation, contributing to acute kidney injury and chronic kidney fibrosis. In the present study, we investigated renoprotective effects of BX-001N, a synthetic polyethylene glycol-conjugated bilirubin nanoparticle, against renal IRI after kidney transplantation. A murine syngeneic kidney transplantation model was used to study renal IRI. BX-001N was administered intravenously at 0 and 2.5 h post-transplantation. Renal functions (creatinine and BUN), histopathological injury, oxidative stress, renal regeneration, and fibrotic changes were assessed at post-transplant day (POD) 1 and 7. BX-001N significantly improved renal function and attenuated renal tissue injury and tubular cell apoptosis at POD 1, following cold IRI. It markedly reduced neutrophil infiltration and suppressed the expression of pro-inflammatory cytokines (TNF-α and IFN-γ) and chemokines (MCP-1 and CXCL2). Antioxidant responses were enhanced, as evidenced by increased expression of heme oxygenase-1 and decreased accumulation of nitrotyrosine. Furthermore, at POD 7, BX-001N promoted renal regeneration with increased Ki-67 and vascular endothelial growth factor expression. It also inhibited renal fibrosis and suppressed epithelial-mesenchymal transition with decreased expression of α-smooth muscle actin, while preserving E-cadherin expression. In conclusion, BX-001N effectively mitigates IRI-induced renal injury by reducing oxidative stress, inflammation, and fibrosis, indicating its potential therapeutic value in kidney transplantation.