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The lack of conventional chemotherapies with sustainable efficacy warrants investigation of novel therapies. Pevonedistat (MLN4924) is a potent and selective small molecule NEDD8\u2010activating enzyme inhibitor. In human activated B\u2010cell\u2010like (ABC) diffuse large B\u2010cell lymphoma, pevonedistat induces lymphoma cell apoptosis, DNA damage and G1 cell cycle arrest by inhibiting the nuclear factor\u2010\u03baB (NF\u2010\u03baB) pathway. Genomic and transcriptomic studies showed that the NF\u2010\u03baB pathway is deregulated in canine DLBCL. Our results showed that pevonedistat treatment significantly reduces the viability of canine DLBCL cells by inducing G1 cell cycle arrest and apoptosis. Pevonedistat treatment inhibits NF\u2010\u03baB pathway activation and downregulates NF\u2010\u03baB target genes in canine DLBCL. Moreover, administration of pevonedistat to mice bearing canine DLBCL xenograft tumours resulted in tumour regression. 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