tsRNAs in HCC: Biology, liquid biopsy and therapy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and there is an urgent need for non-invasive diagnostic tools and effective treatments. Transfer RNA-derived small RNAs (tsRNAs) are a novel class of small non-coding RNAs generated by site-specific cleavage of transfer RNAs. This review summarizes the biogenesis, classification and biological functions of tsRNAs, focusing on their roles in HCC. tsRNAs contribute to multiple cancer hallmarks, including proliferation, resistance to apoptosis, immune modulation, angiogenesis, metastasis, and metabolic reprogramming, through the regulation of signaling pathways, epigenetic control, and translational regulation. Because tsRNAs are highly stable in body fluids, they represent promising liquid biopsy markers. Several specific tsRNAs have shown excellent diagnostic performance, with area under the curve (AUC) values above 0.84 and improved sensitivity when combined with conventional markers such as alpha-fetoprotein (AFP). Preclinical evidence using antagomirs or agomirs to target oncogenic or tumor-suppressive tsRNAs has demonstrated encouraging anti-tumor effects in HCC models. tsRNAs are emerging as valuable diagnostic biomarkers and potential therapeutic targets for HCC. Clinical translation still faces challenges including low delivery efficiency, off-target effects, and a lack of standardized protocols. Future efforts should focus on unified nomenclature, standardized detection methods, and combination strategies with immunotherapy and targeted therapy to advance precision hepatology.