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 CD44 and its isoforms v6 and v10 were progressively upregulated in chronic liver injury, peaking in HCC. CD44-positive hepatocytes increased with fibrosis severity and were abundant in murine liver tumours. In human HCC, CD44 expression was significantly elevated compared to non-tumorous liver and was associated with reduced overall survival. CD44 high 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.