Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role in sorafenib resistance in hepatocellular carcinoma (HCC), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a dysregulated lncRNA in sorafenib-resistant HCC cells. However, the underlying regulatory mechanisms of MALAT1 in sorafenib-resistant HCC cells remain unclear. In the present study, we demonstrated that 5-methylcytosine (m5C) methylation catalyzed by NSUN2 and ALYREF contributed to the RNA stability and upregulation of MALAT1. The NSUN2/ALYREF/MALAT1 signaling axis was activated in sorafenib-resistant cells, and the upregulation of MALAT1 inhibited sorafenib-induced ferroptosis to drive sorafenib resistance. Mechanistically, MALAT1 maintained the mRNA stability of SLC7A11 by directly binding to ELAVL1 and stimulating its cytoplasmic translocation. Furthermore, we explored a new synergetic strategy for the treatment of HCC by combining MALAT1 inhibitor MALAT1-IN1 with sorafenib. The results demonstrated that MALAT1-IN1 significantly enhanced sorafenib efficacy for the treatment of HCC both in vitro and in vivo. Collectively, our work brings new insights into the epigenetic mechanisms of sorafenib resistance and offers an alternative therapeutic strategy targeting ferroptosis for sorafenib-resistant HCC patients.

中文翻译：

---

MALAT1 的 5-甲基胞嘧啶甲基化通过 ELAVL1/SLC7A11 介导的铁死亡促进肝细胞癌对索拉非尼的耐药性


新出现的证据表明，长链非编码 RNA （lncRNA） 在肝细胞癌 （HCC） 的索拉非尼耐药中起关键作用，而 lncRNA 转移相关肺腺癌转录本 1 （MALAT1） 是索拉非尼耐药 HCC 细胞中失调的 lncRNA。然而，MALAT1 在索拉非尼耐药 HCC 细胞中的潜在调节机制仍不清楚。在本研究中，我们证明了 NSUN2 和 ALYREF 催化的 5-甲基胞嘧啶 （m5C） 甲基化有助于 MALAT1 的 RNA 稳定性和上调。NSUN2/ALYREF/MALAT1 信号轴在索拉非尼耐药细胞中被激活，MALAT1 的上调抑制索拉非尼诱导的铁死亡，从而驱动索拉非尼耐药。从机制上讲，MALAT1 通过直接结合 ELAVL1 并刺激其细胞质易位来维持 SLC7A11 的 mRNA 稳定性。此外，我们通过将 MALAT1 抑制剂 MALAT1-IN1 与索拉非尼联合使用，探索了一种治疗 HCC 的新协同策略。结果表明，MALAT1-IN1 在体外和体内均显著增强了索拉非尼治疗 HCC 的疗效。总的来说，我们的工作为索拉非尼耐药的表观遗传机制带来了新的见解，并为索拉非尼耐药的 HCC 患者提供了一种针对铁死亡的替代治疗策略。