Targeting the hyaluronic acid–CD44 axis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a major global health challenge, with rising incidence, frequent development of drug resistance, and limited long-term survival despite advances in systemic therapies. Within the tumor microenvironment, the interaction between hyaluronic acid (HA) and cluster of differentiation 44 (CD44) is linked to tumor progression and therapeutic failure. Accordingly, targeting the HA–CD44 signaling axis represents a promising strategy to overcome resistance. This review highlights potential approaches, including inhibition of HA synthesis, enzymatic HA degradation, CD44 blockade, and HA-based nanocarriers for selective drug delivery, alone or combined with existing therapies. Leveraging HA–CD44 biology may help refine profiling and support the development of more personalized treatments, ultimately enhancing outcomes for HCC patients.