Zhiyao Liu, Yuqiao Wang, Yali Wang, Yucheng Zhang
Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, with high morbidity and mortality rates globally, ranking it among the leading causes of cancer‑related death worldwide. Despite notable advancements in HCC treatment in recent years, high rates of recurrence and treatment resistance remain significant clinical challenges. The development of drug resistance undermines the efficacy of current therapies and leads to poor patient outcomes. However, the specific role and detailed delivery mechanism of exosomal circular RNAs (circRNAs) in mediating this treatment resistance are still largely undefined. circRNAs represent a group of non‑coding RNAs with various biological roles. An increasing number of circRNAs are abnormally expressed in HCC and participate in the malignant progression of HCC, playing a role in HCC treatment resistance. Furthermore, circRNAs can exert additional effects when packaged into exosomes. Exosomes, as signaling molecules of intercellular communication, are enriched with circRNAs, which can be packaged, secreted and transferred to target recipient tumor cells, thereby regulating the development process and drug resistance of cancer. The present comprehensive review aims to summarize how these exosomal circRNAs regulate key hallmarks of cancer in HCC and critically synthesize the current literature, elucidating how exosomal circRNAs modulate therapeutic resistance in HCC and highlighting their potential as biomarkers and therapeutic targets.