Low-Dose MLN4924 Enhances SH-SY5Y Cell Viability and Migration by Targeting SOCS3 Signaling

MLN4924 (pevonedistat), a selective inhibitor of the NEDD8-activating enzyme, has inhibitory effects on various tumors by blockade of the neddylation pathway. Conversely, recent studies show that low-dose MLN4924 exerts pro-survival effects in both cancer cells and neurons, however, its actions on SH-SY5Y cells remain unclear. In this study, the effects of low-dose MLN4924 in SH-SY5Y cells were assessed by CCK-8 and Transwell assay, respectively. SH-SY5Y cells were transfected with enhanced green fluorescent protein plasmid to further observe neurite changes. The expression of SOCS3, p-JAK2 and p-STAT3 were analyzed by Western blot, and the potential interaction between MLN4924 and SOCS3 was explored via in silico molecular docking. Our results showed that 0.1 μM MLN4924 significantly enhanced SH-SY5Y cell viability and migration while concurrently reducing neurite outgrowth. The expression level of SOCS3 was significantly increased in the MLN4924 treatment group compared with the control group, but the phosphorylation levels of JAK2 and STAT3 showed no changes. Molecular docking further predicted that Glu63 of SOCS3 serves as a key residue for MLN4924 binding. Together, low-dose MLN4924 enhances SH-SY5Y cell viability and migration by targeting SOCS3 signaling, independent of JAK2/STAT3 signaling.