Mac‐2 Binding Protein Glycosylation Isomer ( M2BPGi )–Based Risk Stratification Refined by Tumor Metabolic Activity in Hepatocellular Carcinoma

ABSTRACT Aim To evaluate the prognostic significance of preoperative Mac‐2 binding protein glycosylation isomer (M2BPGi) and determine whether tumor metabolic activity provides additional risk stratification after hepatic resection for hepatocellular carcinoma (HCC). Methods We retrospectively analyzed 291 patients with HCC who underwent hepatic resection at a single Japanese institution between 2015 and 2023 and had available preoperative M2BPGi and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography data. Associations with clinicopathological features, recurrence‐free survival (RFS), and overall survival (OS) were evaluated. Results High M2BPGi was associated with impaired liver function and F3–F4 fibrosis but not with tumor‐related features or tumor metabolic activity. In contrast, high tumor metabolic activity was associated with higher des‐ γ ‐carboxy prothrombin (DCP) levels, larger tumors, poor differentiation, microscopic vascular invasion, and intrahepatic metastasis. High M2BPGi and high tumor metabolic activity independently predicted worse RFS (hazard ratio [HR], 1.61; p = 0.0105 and HR, 1.94; p = 0.0023, respectively) and OS (HR, 2.03; p = 0.0042 and HR, 1.93; p = 0.0199, respectively). The dual‐high group had the poorest RFS and OS (both p < 0.0001). In public data analysis, M2BPGi‐related fibrosis and glycolysis‐related signatures were positively correlated with a mechanistic target of rapamycin complex 1 (mTORC1)‐related anabolic signature ( R = 0.439 and R = 0.670, respectively; p < 0.0001), and a high mTORC1‐related signature was associated with worse OS ( p = 0.0074). Conclusions Preoperative M2BPGi identifies fibrosis‐related risk after HCC resection, whereas tumor metabolic activity further distinguishes patients with particularly poor outcomes.