O-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.

Keywords

hepatocellular carcinoma / metabolic dysfunction-associated steatotic liver diseases / O-GlcNAc transferase / O-GlcNAcylation / phosphatase and tensin homolog deleted on chromosome ten

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