Serum metabolomic alterations associated with vascular invasion and early recurrence in hepatocellular carcinoma: a prospective pilot study

Hepatocellular carcinoma (HCC) is a lethal malignancy and microvascular invasion (mVI) is a critical indicator of aggressive biology. Most patients experience early recurrence (ER)—relapse within two years of surgery—which is significantly more detrimental to prognosis than late recurrence. Cancer cells exhibit profound metabolic reprogramming to drive tumor progression. This study aimed to utilize metabolomic analysis to unravel serum metabolomic alterations associated with mVI and ER in HCC. In this prospective study of 92 HCC patients undergoing curative resection, serum samples were analyzed via Ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) to quantify acylcarnitines, phospholipids, and amino acids. Receiver-operating characteristic (ROC) analysis was conducted to evaluate the predictive power of these altered metabolites. Regarding mVI, serum levels of C6:1 and hydroxydodecanoyl-L-carnitine were significantly lower in mVI-positive patients ( P = 0.028). Combining these with tumor size yielded an AUROC of 0.764 ( P < 0.001). For ER, a distinct postoperative systemic lipidomic reprogramming involved 33 metabolites, most notably ether-linked phospholipids like PCe 44:5 ( P < 0.001, AUROC 0.760). Significant depletion of histidine ( P = 0.012) and valine ( P = 0.035) was also observed. An integrated 7-marker panel achieved an AUROC of 0.793 ( P < 0.001) for predicting ER. Metabolic reprogramming, characterized by acylcarnitine depletion in mVI and ether-lipid elevation in ER, serves as a central driver of HCC evolution. These high-accuracy metabolic signatures provide potent non-invasive tools for identifying mVI and postoperative recurrence risk, offering a biological rationale for targeting lipid metabolism to prevent relapse.