G6PDCSV circulating tumor cells associated with portal vein tumor thrombus formation via EMT-ferroptosis crosstalk: a dual biomarker for therapeutic efficacy and prognosis prediction in hepatocellular carcinoma.

Portal vein tumor thrombus (PVTT) is a major contributor to recurrence, metastasis, and poor prognosis in hepatocellular carcinoma (HCC). Effective early detection and therapeutic strategies for PVTT are lacking. In our ongoing investigation, we identified cell surface vimentin-positive (CSV) CTCs as a key subpopulation enriched in HCC patients with PVTT, whereas conventional EpCAM CTCs exhibited limited clinical relevance. Integrated multi-omics analyses further revealed that tumor cells within the primary lesion exhibiting both epithelial-mesenchymal transition (EMT) and ferroptosis-associated signatures are more likely to intravasate and contribute to PVTT formation. Notably, G6PD was identified as a ferroptosis-related marker specifically enriched in this EMT-like tumor cell subset, suggesting its functional involvement in PVTT pathogenesis. Clinically, elevated levels of G6PDCSV CTCs were associated with poor responses to targeted immunotherapy. Importantly, the identification of CSV also provides a rationale for developing CSV-guided delivery systems, enabling targeted silencing of PVTT-associated molecular drivers such as G6PD. Collectively, our findings highlight G6PDCSV CTCs as a dual-function biomarker for both PVTT risk stratification and treatment response monitoring, offering a novel strategy for the precision management of advanced HCC with PVTT involvement.