BACKGROUND: Our previous study demonstrated that olfactory mucosa mesenchymal stem cell (OM-MSC) neuronal differentiation can reduce neural damage following intracerebral hemorrhage (ICH). However, the mechanisms that regulate OM-MSC neuronal differentiation to mitigate ICH-induced brain injury remain unclear. METHODS: The ICH model was established through autologous blood injection to evaluate the impact of OM-MSCs on brain injury, using the mNSS method, TUNEL, and Nissl staining, as well as the Western blot assay. qPCR, Western blotting, flow cytometry, and immunofluorescence assays were employed to assess the neuronal differentiation of OM-MSCs. The SUMOylation assay was conducted to investigate the relationship between IGF2BP2 and SENP1. RIP, RNA pull-down, and mRNA stability assays were performed to analyze the molecular interaction network involving SENP1, IGF2BP2, and SOX11. RESULTS: IGF2BP2 enhanced the protective effects of OM-MSCs against ICH-induced brain injury, as demonstrated by a significant reduction in brain edema, mNSS scores, and apoptosis, along with improved neuronal survival. Furthermore, the overexpression of IGF2BP2 increased the expression of Tuj-1, MAP2, NF200, and NeuN, while decreasing GFAP and ALDH1L1 levels, suggesting the stimulatory effects of IGF2BP2 on the neuronal differentiation of OM-MSCs. Mechanistically, SENP1 enhanced IGF2BP2 expression through SUMO1-induced IGF2BP2 SUMOylation. Additionally, IGF2BP2 functioned as an RNA-binding protein for SOX11, thereby increasing SOX11 levels. The depletion of IGF2BP2 negated the SENP1-induced neuronal differentiation of OM-MSCs. The overexpression of SOX11 mitigated the inhibitory effects of IGF2BP2 silencing on OM-MSC neuronal differentiation. CONCLUSION: The SENP1/IGF2BP2/SOX11 axis played a crucial role in the neuronal differentiation of OM-MSCs and ameliorated brain damage caused by ICH.