CD44 upregulation in chronic liver disease marks the transition to hepatocellular carcinoma and portends poor prognosis

BACKGROUND: Hepatocellular carcinoma (HCC) often arises from chronic liver disease, but early biomarkers of malignant transformation are lacking. CD44, a transmembrane glycoprotein with multiple isoforms, has been implicated in cancer progression and immune modulation. METHODS: We analysed CD44 expression in mouse models of chronic and acute liver injury and assessed its clinical relevance in human HCC using bulk and single-cell transcriptomic datasets. RESULTS: tumours showed enrichment in oncogenic signalling pathways and greater infiltration of immunosuppressive cells, including M2 macrophages and Th2 cells. Single-cell RNA-seq confirmed CD44 expression in both tumour and immune cells, linking it to a protumor immune microenvironment. CONCLUSIONS: CD44 is a promising early biomarker of hepatocarcinogenesis and a potential therapeutic target. Its expression reflects disease progression from fibrosis to cancer and is associated with poor prognosis and immune evasion in HCC.