Although UFL1 expression was unaltered in the absence of LRP1, our results demonstrated that silencing of UFL1 exerted anti‐tumor effects in HCC cells with LRP1 knockdown by consequent reactions: 1) reducing cellular O‐GlcNAcylation levels through stabilization of OGA; 2) attenuating NF‐κB p65 O‐GlcNAcylation; 3) promoting apoptosis of HCC cells by inhibiting Bcl‐2 and enhancing Bax expression; and 4) suppressing the proliferation and migration abilities of HCC cells. This evidence concerns the gene NFKB1 and neoplasm.