Revisiting cholesterol metabolism in hepatocellular carcinoma: a hidden driver of systemic therapy response

Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related mortality worldwide and poses a substantial challenge in the field of oncology. The majority of patients are diagnosed at advanced stages of the disease, where systemic therapies remain the primary treatment modality. These interventions, however, are frequently constrained by limited efficacy and considerable adverse effects, highlighting the pressing need for more precise and effective therapeutic strategies. Emerging evidence has identified cholesterol as a critical factor in HCC pathogenesis, influencing key processes such as tumor initiation, cellular proliferation, immune dysregulation, and metastatic progression. Moreover, disruptions in cholesterol metabolism have been increasingly implicated in resistance to systemic treatments. This review provides a concise overview of therapeutic approaches targeting cholesterol in HCC and examines the influence of cholesterol metabolism on the efficacy of systemic therapies, particularly those currently considered standard of care. Finally, we discuss existing challenges and propose future directions for integrating cholesterol-lowering strategies to enhance treatment outcomes in patients with HCC.