Dual Escape From Disulfidptosis and Ferroptosis Drives Highly Aggressive, Hypermetabolic Hepatocellular Carcinoma

AIM: The cystine/glutamate antiporter xCT facilitates cystine uptake and glutathione synthesis and suppresses ferroptosis. However, its role in hepatocellular carcinoma (HCC), particularly in glucose metabolism and disulfidptosis, remains unclear. We examined the prognostic value of xCT expression and tumor 18F-fluorodeoxyglucose (FDG) uptake as well as their association with tumor biology. METHODS: We retrospectively analyzed 345 patients with HCC who underwent hepatic resection. Immunohistochemical staining for xCT was performed in all 345 cases, and its associations with clinicopathological characteristics and survival were evaluated. Among these, 108 patients also underwent preoperative 18F-FDG positron emission tomography/computed tomography (PET/CT). In this subset, tumor FDG uptake was quantified and its relationship with xCT expression and patient prognosis was assessed. RESULTS: Patients with xCT-positive tumors had significantly worse overall survival compared with those with xCT-negative tumors (10-year, 42.6% vs. 75.2%; log-rank test, p < 0.0001). Among 108 patients with HCC who underwent PET/CT, xCT positivity was an independent predictor of poor prognosis in multivariate analysis (hazard ratio, 3.17; 95% confidence interval, 1.47-6.87; p = 0.0034). In addition, xCT expression correlated with FDG uptake (p = 0.0335). Importantly, tumors that were both xCT-positive and had high FDG uptake exhibited the poorest prognosis (log-rank test, p = 0.0405). CONCLUSIONS: High xCT expression combined with elevated FDG uptake may identify a subset of patients with HCC who have poor prognoses and dual resistance to ferroptosis and disulfidptosis. These findings highlight the potential of xCT as both a prognostic biomarker and therapeutic target for aggressive HCC.