积累的证据已经证实转移RNA（tRNA）的修饰和肿瘤进展之间存在联系。本研究是首次探讨tRNA甲基转移酶5（TRMT5）在肝细胞癌（HCC）进展中催化线粒体tRNA的m1G37修饰的作用。通过基于生物信息学和临床分析，我们发现TRMT5表达在HCC中上调，这与恶劣预后相关。沉默TRMT5能够减弱HCC在体内和体外的增殖和转移，这可以部分解释由ECAR和OCR下降引起的。机理上, 我们发现抑制TRMT5通过提高细胞氧含量来预防HIF-1α稳定，进而使HIF-1信号通路失活。此外, 我们的数据表明抑制TRMT5使HCC对多柔比星更敏感，通过调节HIF-‍1α来实现。总之，我们的研究揭示了针对TRMT5可以抑制HCC的进展，并增加肿瘤细胞对化疗药物的敏感性。因此，TRMT5可能是一个致癌基因，并且可以作为HCC治疗的潜在靶点。

Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.