Systemic lupus erythematosus (SLE) is a severe autoimmune disorder characterized by systemic inflammatory response, autoantibody accumulation, and organ damage. The dysregulation of double-negative (DN) T cells is a crucial factor in SLE pathogenesis. Neddylation, a significant type of protein post-translational modification (PTM), has been shown to regulate T cell-mediated immune responses. However, its role in SLE remains unclear. This study found that inactivating neddylation using MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetically abrogating Ube2m in T cells reduced DN T cell accumulation and attenuated murine lupus development. Further research revealed that inactivating neddylation blocked Bim ubiquitination degradation and maintained Bim levels in DN T cells, leading to apoptosis of accumulated DN T cells in lupus mice. Double knockout (DKO) lupus-prone mice (Ube2m/Bim−/−) were generated, and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Clinically, SLE patients exhibited increased DN T cell accumulation and reduced apoptosis, with decreased Bim levels and elevated Cullin1 neddylation levels. Inhibition of neddylation with MLN4924 induced Bim-dependent apoptosis in DN T cells isolated from SLE patients. These findings suggest that neddylation inactivation promotes Bim-mediated DN T cell apoptosis and attenuates lupus progression, providing a novel therapeutic target for SLE.Systemic lupus erythematosus (SLE) is a severe autoimmune disorder characterized by systemic inflammatory response, autoantibody accumulation, and organ damage. The dysregulation of double-negative (DN) T cells is a crucial factor in SLE pathogenesis. Neddylation, a significant type of protein post-translational modification (PTM), has been shown to regulate T cell-mediated immune responses. However, its role in SLE remains unclear. This study found that inactivating neddylation using MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetically abrogating Ube2m in T cells reduced DN T cell accumulation and attenuated murine lupus development. Further research revealed that inactivating neddylation blocked Bim ubiquitination degradation and maintained Bim levels in DN T cells, leading to apoptosis of accumulated DN T cells in lupus mice. Double knockout (DKO) lupus-prone mice (Ube2m/Bim−/−) were generated, and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Clinically, SLE patients exhibited increased DN T cell accumulation and reduced apoptosis, with decreased Bim levels and elevated Cullin1 neddylation levels. Inhibition of neddylation with MLN4924 induced Bim-dependent apoptosis in DN T cells isolated from SLE patients. These findings suggest that neddylation inactivation promotes Bim-mediated DN T cell apoptosis and attenuates lupus progression, providing a novel therapeutic target for SLE.