MicroRNAs in hepatocellular carcinoma: Diagnostic, therapeutic, and prognostic insights: A comprehensive review

Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer and is a primary cause of cancer-related mortality worldwide. Its late-stage diagnosis severely limits treatment options, emphasizing the importance of early diagnosis and prognosis for improving patient survival. This review underscores the regulatory roles of microRNAs (miRNAs) in HCC progression and their potential as biomarkers for diagnosis, prognosis, and therapy. Notable miRNAs, such as miR-122, miR-21, and miR-221, have emerged as important biomarkers; the up-regulation of miR-21 and miR-155 is linked to poor prognosis and metastasis. Additionally, exosomal miRNAs like miR-210 and miR-638 are promising non-invasive diagnostic options. A significant research gap exists regarding how exosomal miRNAs prepare other organs for metastasis before the tumor becomes detectable. Furthermore, miRNA-based therapies, including mimics and inhibitors, show promise in preclinical models, although successful clinical application will depend on addressing delivery challenges. Current strategies involving lipid nanoparticles, viral vectors, exosomes, and minicircles each have unique advantages and limitations. Ongoing clinical trials (e.g., NCT04965259, NCT05148572) are validating circulating and exosomal miRNA signatures for early detection and recurrence prediction in HCC. In conclusion, miRNAs are integral to HCC pathogenesis and present significant opportunities for diagnostic and therapeutic advancements. The review advances our understanding by integrating miRNA functions with tumor microenvironment biology, highlighting the potential for developing multi-analytical panels to enhance diagnostic precision and addressing challenges in miRNA therapy delivery.