106 This study is led by Dr Jianming Li and Dr Jing Huang from the Department of Pathology at Soochow Medical College, Soochow University. It focuses on O-GlcNAcylation, a dynamic and reversible post-translational modification regulated by two key enzymes: O-GlcNAc Transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes it. This modification plays an important role in controlling protein stability, activity, and subcellular localisation, and is involved in essential cellular processes such as metabolism and cell proliferation. The study, published in the journal MedComm – Oncology. In this study, the researchers investigated the role of OGT-mediated O-GlcNAcylation in Metabolic Dysfunction-Associated Steatotic Liver Disease-related Hepatocellular Carcinoma (MASLD-HCC). They identified the tumour suppressor PTEN as a critical target of this modification. Through analysis of patient samples and public databases, the team found that OGT expression is significantly higher in MASLD-HCC tissues compared to adjacent non-tumour tissues, and its high expression correlates with advanced tumour stages. Using liver-specific Ogt knockout mice and xenograft models, they demonstrated that OGT promotes liver tumour progression: deletion of Ogt slows tumour growth, while OGT overexpression accelerates tumour formation (see Figure 2). Mechanistically, the researchers found that OGT directly interacts with PTEN and modifies it at the T382 residue. This O-GlcNAcylation exerts dual effects on PTEN: it competitively inhibits phosphorylation (a modification that stabilises PTEN) at the same site, thereby promoting PTEN ubiquitination and proteasomal degradation; simultaneously, it impairs PTEN’s intrinsic phospholipase activity. As a result, PTEN function is compromised, leading to activation of the PI3K/Akt signalling pathway and enhanced proliferation of liver cancer cells (see Figure 3). Notably, the team also explored how the tumour microenvironment affects this pathway and its therapeutic implications. Under lipid-rich and hypoxic conditions (common features of liver tumours), OGT expression and PTEN O-GlcNAcylation are both elevated. To counter this effect, they tested the therapeutic potential of targeting OGT. Treatment with the OGT inhibitor OSMI-1 suppressed tumour growth and combining it with the PI3K inhibitor LY294002 produced an even greater antitumour effect. These results underscore the value of disrupting both metabolic regulators and downstream proliferative signalling in developing effective treatments for MASLD-related liver cancer (see Figure 4). By comprehensively analysing OGT’s expression pattern, its regulation of PTEN, and its therapeutic potential, this study offers new insights into the molecular mechanisms driving MASLD-HCC. It identifies both OGT and PTEN as potential therapeutic targets and lays the groundwork for developing O-GlcNAcylation-based therapies for liver cancer associated with metabolic liver disease.