<i>O</i> ‐GlcNAc Transferase Promotes Metabolic Dysfunction‐Associated Steatotic Liver Disease‐Related Hepatocellular Carcinoma by Facilitating the Degradation of PTEN

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a major risk factor for hepatocellular carcinoma (HCC), yet treatment options for advanced disease remain limited. O ‐GlcNAc transferase (OGT), the enzyme catalyzing O ‐GlcNAcylation, has been implicated in tumorigenesis, but its pro‐cancer mechanism in MASLD‐HCC remains poorly defined. Here, we show that OGT expression is significantly upregulated during MASLD‐HCC progression and negatively regulates the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) both in vivo and in vitro . Mechanistically, OGT catalyzes O ‐GlcNAcylation of PTEN at T382, which competitively inhibits the phosphorylation at the same residue. This modification promotes PTEN ubiquitination and accelerates its degradation. Importantly, O ‐GlcNAcylation of PTEN simultaneously impairs its intrinsic phospholipase activity. These dual effects compromise PTEN function, leading to activation of PI3K/Akt signaling pathway and enhanced tumor cell proliferation and migration. Moreover, pharmacological inhibition of OGT suppresses tumor growth and, when combined with PI3K/Akt pathway inhibitors, produces additive antitumor effects. These findings reveal a novel mechanism by which OGT‐mediated O ‐GlcNAcylation destabilizes and inactivates PTEN, driving MASLD‐HCC progression. They also highlight OGT and PTEN as promising therapeutic targets for developing novel strategies against HCC.