The tRNA-Derived Fragment tRF-E Promotes Ferroptosis in Hepatocellular Carcinoma to Suppress Tumor Progression

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. tRNA-derived fragments (tRF) have been shown to play various roles in HCC tumorigenesis. In the current study, we identified that tRF-Glu-i-0545 (tRF-E), which is derived from an internal region of tRNA-Glu, is a tumor suppressor in HCC. tRF-E was significantly downregulated in HCC samples, and low tRF-E levels were associated with poor prognosis of patients with HCC from multiple cohorts. tRF-E sensitized HCC cells to ferroptosis in vitro and in vivo. Mechanistically, tRF-E interrupted binding of VDAC2 to the E3 ligase Nedd4 to block ubiquitination and promote VDAC2 stabilization, which enhanced iron-dependent lipid peroxidation and ultimately triggered ferroptosis. The RNA-binding protein SRSF6 cleaved tRNAGluTTC to generate tRF-E, and hypoxia inhibited tRF-E biogenesis by suppressing SRSF6. Specifically, hypoxia-induced alternative splicing of the SRSF6 mRNA produced a long transcript containing a poison cassette exon, which led to nonsense-mediated mRNA decay. In conclusion, this study identifies a tumor suppressive tRF that enhances ferroptosis sensitivity in HCC and illustrates the potentials of tRFs in cancer treatments. SIGNIFICANCE: Hypoxia promotes ferroptosis resistance in hepatocellular carcinoma by downregulating the tRNA-derived fragment tRF-E to suppress VDAC2 stability, highlighting activation of the tRF-E/VDAC2 axis as a promising therapeutic strategy in liver cancer.