NSun2‐Mediated tsRNAs Alleviate Liver Fibrosis via FAK Dephosphorylation

ABSTRACT Sinusoidal capillarization – key symptoms of liver fibrosis progression – represents potential therapeutic targets. tRNA modification‐mediated tRNA‐derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA methyltransferase, generates a significant number of tsRNAs. However, the role of NSun2 and its mediated tsRNAs in liver fibrosis remains unclear. In this study, NSun2 deficiency was found to inhibit sinusoidal capillarization, alleviating liver fibrosis. Furthermore, endothelial cell angiogenesis and migration were disrupted in NSun2 knockout mice. Mechanistically, reduced NSun2 expression led to alterations in the functional tsRNAs tRF‐1‐S25 and tRF‐5‐V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK – crucial clinical targets. Moreover, intravenous injection of tRF‐1‐S25 and tRF‐5‐V31 inhibitor rescued liver fibrosis in mice. In conclusion, tsRNAs generated by NSun2‐mediated modification of tRNAs inhibit sinusoidal capillarization. Furthermore, targeting the DUSP1/FAK/p‐FAK pathway offers an innovative approach to treat this disease.