Abstract：
Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by complex heterogeneity and drug resistance. Resistance to ferroptosis is closely related to the progression of HCC. While HCC tumors vary in their sensitivity to ferroptosis, the precise factors underlying this heterogeneity remain unclear. In this study, we sought to elucidate the mechanisms that contribute to ferroptosis resistance in HCC. Whole-genome CRISPR/Cas9 screen using a subtoxic concentration (IC20) of ferroptosis inducer erastin in the HCC cell line Huh7 revealed TRIM34 as a critical driver of ferroptosis resistance in HCC. Further investigation revealed that TRIM34 suppresses ferroptosis in HCC cells, promoting their proliferation, migration, and invasion both in vitro and in vivo. Furthermore, TRIM34 expression is elevated in HCC tumor tissues, correlating with a poor prognosis. Mechanistically, TRIM34 directly interacts with Up-frameshift 1 (UPF1), a core component of the nonsense-mediated mRNA decay (NMD) pathway, to promote its ubiquitination and degradation. This interaction suppresses GPX4 transcript degradation, thus promoting the protein levels of this critical ferroptosis suppressor in HCC. In light of the close crosstalk between ferroptosis and the adaptive immune response in cancer, HCC cells with targeting knockdown of TRIM34 exhibited an improved response to anti-PD-1 treatment. Taken together, the TRIM34/UPF1/GPX4 axis mediates ferroptosis resistance in HCC, thereby promoting malignant phenotypes. Targeting TRIM34 may thus represent a promising new strategy for HCC treatment.
摘要：
肝细胞癌（HCC）是一种常见的恶性肿瘤，具有复杂的异质性和耐药性。对铁性凋亡的抵抗与HCC的进展密切相关。虽然HCC肿瘤对铁凋亡的敏感性不同，这种异质性背后的确切因素仍不清楚.在这项研究中,我们试图阐明导致HCC铁凋亡抵抗的机制。在HCC细胞系Huh7中使用亚毒性浓度（IC20）的铁凋亡诱导擦除素进行的全基因组CRISPR/Cas9筛选显示，TRIM34是HCC中铁凋亡抗性的关键驱动因素。进一步的研究表明，TRIM34抑制肝癌细胞的铁凋亡，促进它们的扩散，迁移,和体内外侵袭。此外，TRIM34在肝癌肿瘤组织中表达升高，与预后不良有关。机械上,TRIM34直接与上移码1(UPF1)交互，无义介导的mRNA衰减（NMD）途径的核心组成部分，促进其泛素化和降解。这种相互作用抑制GPX4转录物降解，从而促进HCC中这种关键的铁凋亡抑制因子的蛋白质水平。鉴于癌症中铁死亡与适应性免疫反应之间的紧密串扰，具有TRIM34靶向敲低的HCC细胞表现出抗PD-1治疗的改善反应。一起来看,TRIM34/UPF1/GPX4轴介导HCC的铁凋亡抗性，从而促进恶性表型。因此，靶向TRIM34可能代表了一种有前途的HCC治疗新策略。
