In summary, our findings first demonstrated the chemopreventive effect of the AKT inhibitor MK2206 2HCl on the 4NQO-induced mouse tongue carcinogenesis model, which may be mediated by inhibiting tumor growth, angiogenesis, and MC infiltration and through suppressing the MMP-9/RhoC signaling pathway, autophagy, and apoptosis. This evidence concerns the gene RHOC and neoplasm.