tsRNAs (tRNA-derived small RNAs), as products of the stress response, exert considerable influence on stress response and injury regulation. However, it remains largely unclear whether tsRNAs can ameliorate liver injury. Here, we demonstrate the roles of tsRNAs in alleviating liver injury by utilizing the loss of NSun2 (NOP2/Sun domain family, member 2) as a tsRNAs-generating model. Mechanistically, the loss of NSun2 reduces methyluridine-U5 (m⁵U) and cytosine-C5 (m⁵C) of tRNAs, followed by the production of various tsRNAs, especially Class I tsRNAs (tRF-1s). Through further screening, we show that tRF-Gln-CTG-026 (tG026), the optimal tRF-1, ameliorates liver injury by repressing global protein synthesis through the weakened association between TSR1 (pre-rRNA-processing protein TSR1 homolog) and pre-40S ribosome. This study indicates the potential of tsRNA-reduced global protein synthesis in liver injury and repair, suggesting a potential therapeutic strategy for liver injury.

tsRNA（tRNA衍生的小RNA）作为应激反应的产物，对应激反应和损伤调节具有相当大的影响。然而，目前尚不清楚 tsRNA 是否可以改善肝损伤。在这里，我们利用NSun2（NOP2/Sun 结构域家族，成员 2）的缺失作为 tsRNA 生成模型，展示了 tsRNA 在减轻肝损伤中的作用。从机制上讲， NSun2的丢失会减少tRNA的甲基尿苷-U5 (m ⁵ U)和胞嘧啶-C5 (m ⁵ C)，随后产生各种tsRNA，尤其是I类tsRNA (tRF-1s)。通过进一步筛选，我们发现 tRF-Gln-CTG-026 (tG026)（最佳 tRF-1）通过 TSR1（前 rRNA 加工蛋白 TSR1 同源物）和前 rRNA 加工蛋白之间的减弱关联，抑制整体蛋白质合成，从而改善肝损伤。 -40S核糖体。这项研究表明了 tsRNA 减少的整体蛋白质合成在肝损伤和修复中的潜力，提出了肝损伤的潜在治疗策略。