Given that DAPT administration and β∆‐chain overexpression counterregulated cellular O‐GlcNAcylation levels, we hypothesized that LRP1‐ICD derived from LRP1 cleavage may increase the expression of a specific deubiquitinase or decrease the expression of a specific ubiquitinase that affects the stability and degradation of OGA, thereby affecting global O‐GlcNAcylation levels and HCC formation. This evidence concerns the gene LRP1 and hepatocellular carcinoma.