Liver cancer stem cells as novel diagnostic biomarkers.

Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, remains a major global health challenge because of its late diagnosis, high recurrence rate, and limited therapeutic response. Recent advances in cancer biology have identified liver cancer stem cells (LCSCs) as a subpopulation within tumors that possess self-renewal capacity, tumorigenic potential, and resistance to conventional therapies. These cells are characterized by distinct surface markers, such as CD133, EpCAM, CD44, CD90, and ALDH1, and aberrant activation of signaling pathways, including the Wnt/β-catenin, Notch, Hedgehog, and TGF-β pathways. Emerging evidence suggests that LCSCs not only contribute to tumor initiation and progression but also serve as novel diagnostic biomarkers for early detection, prognosis stratification, and therapeutic monitoring in HCC. Circulating LCSC-derived extracellular vesicles and transcriptomic signatures offer promising avenues for noninvasive liquid biopsy approaches. This review synthesizes current findings on the molecular characterization of LCSCs, their clinical relevance, and the potential integration of LCSC biomarkers into precision oncology workflows. Targeting LCSCs may increase diagnostic accuracy and pave the way for more effective, stem cell-directed therapies in liver cancer management.