MLN4924 suppresses kidney renal clear cell carcinoma progression through coordinated inhibition of Cullin1 neddylation and PSMB10-associated NF-κB inflammatory signaling.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is characterized by malignant progression, inflammatory signaling, and therapeutic resistance. This study investigated whether MLN4924, a selective NEDD8-activating enzyme inhibitor, suppresses KIRC progression through coordinated regulation of Cullin1 neddylation, PSMB10 expression, and NF-κB signaling. METHODS: KIRC cells were treated with MLN4924, followed by Western blotting, transcriptomic sequencing, pathway enrichment analysis, PSMB10 knockdown, and NF-κB pathway assessment. Complementary PSMB10 overexpression rescue experiments, together with colony formation and Transwell assays, were performed to test whether restoration of PSMB10 could reverse MLN4924-induced NF-κB inhibition and associated malignant phenotypes. A 786-O nude mouse xenograft model was used to evaluate the in vivo antitumor effects, tolerability, histological alterations, and molecular mechanisms of MLN4924. RESULTS: MLN4924 inhibited renal cancer cell growth and markedly reduced Cullin1-NEDD8 and PSMB10 protein levels. Transcriptomic analysis revealed extensive remodeling of lipid and sterol metabolism, extracellular matrix organization, cytokine and inflammatory signaling, growth factor-related pathways, and DNA replication-associated processes. MLN4924 treatment and PSMB10 knockdown both suppressed p65 phosphorylation, while combined intervention further inhibited phosphorylation of p65, IKKα/β, and IκBα. Conversely, PSMB10 overexpression partially restored p65 phosphorylation in MLN4924-treated ACHN and 786-O cells and significantly recovered colony formation, migration, and invasion. In vivo, MLN4924 significantly reduced tumor volume and weight, with an inhibition rate exceeding 30% and acceptable tolerability. Treated tumors showed increased apoptosis and necrosis, decreased Cullin-NEDD8, PSMB10, phospho-p65, TNF-α, IL-6, EMT/ECM remodeling markers, and proliferation-related proteins, and enhanced apoptotic signaling. CONCLUSION: MLN4924 suppresses KIRC progression through inhibition of neddylation and attenuation of PSMB10-associated IKK/IκB/p65 NF-κB inflammatory signaling.