Spinal cord injury (SCI) represents a significant medical challenge, with limited therapeutic options and suboptimal outcomes. This study investigates the therapeutic potential of low-dose lipopolysaccharide (LD-LPS) in SCI, aiming to elucidate the underlying molecular mechanisms. An in vivo SCI model was established, and the effects of LD-LPS, 2-D08, and RNF4 on nerve injury were assessed using Nissl staining, dihydroethidium (DHE) staining, and Basso, Beattie, Bresnahan (BBB) locomotor scores. In vitro models of SCI were also developed, treated with LD-LPS, and transfected with si-KEAP1, si-RNF4, or RNF4-overexpression vectors. RNF4 and Nrf2 expression levels were measured via immunofluorescence staining, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and Western blot analysis. Cell viability and reactive oxygen species (ROS) production were assessed using the Cell Counting Kit-8 (CCK-8) and 2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA) assays. Oxidative stress was evaluated by measuring the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH). Immunoprecipitation was used to determine the SUMOylation level of SUMO-Nrf2, and the interaction between RNF4 and Nrf2 was analyzed through Split-BioID. LD-LPS demonstrated significant neuroprotective effects by mitigating oxidative stress following SCI. Mechanistically, RNF4 was identified as a critical regulator of Nrf2 SUMOylation, modulating its nuclear translocation. Genetic silencing of RNF4, in conjunction with LD-LPS treatment, alleviated SCI-induced neuronal damage, reduced oxidative stress, and promoted motor function recovery. Conversely, RNF4 overexpression exacerbated SCI injury, highlighting its central role in Nrf2 degradation. These results suggest that LD-LPS mitigates ROS production in SCI by modulating RNF4-mediated SUMOylation of Nrf2. These findings provide initial evidence for the molecular mechanisms underlying LD-LPS preconditioning in SCI.