Circular RNAs (circRNAs) are a novel and unique class of noncoding RNAs that are back-spliced from pre-mRNAs. It has been confirmed that circRNAs are involved in various malignant behaviors of hepatocellular carcinoma (HCC). However, the role of circRNA in the regulation of ferroptosis and the underlying mechanism remain unknown. Here, cIARS (hsa_circ_0008367) was found to be the most highly expressed circRNA after sorafenib (SF) treatment in HCC cells. Small interfering RNA against cIARS (si-cIARS) significantly suppressed the cellular sensitivity to SF or Erastin through inactivating ferroptosis, which may be partially attributed to the inhibition of autophagy and ferritinophagy. Prediction analysis and mechanistic identification revealed that cIARS physically interacted with RNA binding protein (RBP) ALKBH5, which was a negative regulator of autophagic flux in HCC. The dissociation of BCL-2/BECN1 complex, mediated by ALKBH5 silencing was effectively blocked by si-cIARS. Furthermore, the inhibition of ferroptotic events, autophagic flux and ferritinophagy resulted from si-cIARS, were significantly rescued by ALKBH5 downregulation. Overall, cIARS may be an important circRNA, positively regulating SF-induced ferroptosis through suppressing the ALKBH5-mediated autophagy inhibition.

环状 RNA (circRNA) 是一类新颖且独特的非编码 RNA，由前 mRNA 反向剪接而成。已证实circRNA参与肝细胞癌（HCC）的多种恶性行为。然而，circRNA在铁死亡调节中的作用及其潜在机制仍不清楚。在这里，cIARS (hsa_circ_0008367) 被发现是 HCC 细胞中索拉非尼 (SF) 处理后表达最高的 circRNA。针对cIARS的小干扰 RNA (s- cIARS ) 通过灭活铁死亡来显着抑制细胞对 SF 或 Erastin 的敏感性，这可能部分归因于自噬和铁蛋白自噬的抑制。预测分析和机制鉴定表明，cIARS与 RNA 结合蛋白 (RBP) ALKBH5 发生物理相互作用，后者是 HCC 中自噬流的负调节因子。由 ALKBH5 沉默介导的 BCL-2/BECN1 复合物的解离被 sicIARS 有效阻断。此外， sicIARS引起的铁死亡事件、自噬通量和铁蛋白自噬的抑制可通过 ALKBH5 下调得到显着缓解。总体而言，cIARS可能是一种重要的 circRNA，通过抑制 ALKBH5 介导的自噬抑制来正向调节 SF 诱导的铁死亡。