铁死亡是一种重要的调控性细胞死亡方式。其抑制与肝细胞癌（HCC）中的治疗抵抗和预后不良密切相关。先前的报告表明铁死亡是一种高度依赖选择性自噬（如铁蛋白自噬、脂质自噬和时钟自噬）的生物过程。我们的研究还发现，在多靶向酪氨酸激酶抑制剂（TKIs）治疗下，内质网相关自噬介导的铁死亡在HCC细胞中起到了作用。在本研究中，我们发现了家族序列相似性134成员B（FAM134B）的同源环状RNA（circRNA），即hsa_circ_0128505（在本研究中缩写为circFAM134B），被鉴定为特异性靶向内质网相关自噬以促进乐伐珠单抗（LV）诱导的铁死亡。我们使用活性氧化物（ROS）、Fe2+、丙二醛（MDA）和蛋白质印迹（WB）实验在HCC细胞中验证了这一观点。RNA pull-down和质谱分析表明，circFAM134B和FAM134B mRNA富集了几个共有的相互作用蛋白。其中，多聚（A）结合蛋白质4（PABPC4）被鉴定为富集最多的结合伴侣。它被证明是反对后义介导的mRNA衰变（NMD）机制的一种新型拮抗剂。我们随后应用了RNA免疫共沉淀（RIP）、RNA pull-down、荧光素酶报告基因和NMD报告基因实验进一步探索了circFAM134B-PABPC4-FAM134B轴在HCC细胞中的确切作用和潜在机制。circFAM134B被证实是一种能与PABPC4竞争性相互作用的海绵体，从而影响FAM134B mRNA的无意义衰变。我们的结果为HCC的综合治疗提供了新证据和策略。

Ferroptosis is an important mode of regulated cell death (RCD). Its inhibition is closely related to therapeutic resistance and poor prognosis in hepatocellular carcinoma (HCC). Previous reports have demonstrated ferroptosis as a biological process highly dependent on selective autophagy, such as ferritinophagy, lipophagy, and clockophagy. Our study also revealed a role for ER-phagy-mediated ferroptosis in HCC cells treated with multi-targeted tyrosine kinase inhibitors (TKIs). In the current study, we found that the homologous circular RNA (circRNA) of the family with sequence similarity 134, member B (FAM134B), hsa_circ_0128505 (was abbreviated as circFAM134B in the present study), was identified to specifically target ER-phagy to promote lenvatinib (LV)-induced ferroptosis using reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), and western blot (WB) assays in HCC cells. RNA pull-down and mass spectrometry analyses suggested that circFAM134B and FAM134B mRNA were enriched with several common interacting proteins. Among them, poly (A) binding protein cytoplasmic 4 (PABPC4) was identified as the most enriched binding partner. It was proven to be a novel antagonist against the nonsense-mediated mRNA decay (NMD) mechanism. We then applied RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter, and NMD reporter gene assays to further explore the exact role and underlying mechanism of circFAM134B-PABPC4-FAM134B axis in HCC cells. circFAM134B was confirmed as a sponge that competitively interacted with PABPC4, thereby influencing FAM134B mRNA nonsense decay. Our results provide novel evidences and strategies for the comprehensive treatment of HCC.