Ferroptosis, an iron-dependent regulated cell death caused by excessive lipid peroxide accumulation, has emerged as a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In this study, we identified the long non-coding RNA RGMB-AS1 as a key regulator of ferroptosis in NSCLC. Mechanistically, RGMB-AS1 interacted with heme oxygenase 1 (HMOX1) and prevented its ubiquitination by the E3 ligase TRC8, leading to increased HMOX1 stability and enhanced ferroptosis. Additionally, RGMB-AS1 bound to the 82–87 amino acid region of N-alpha-acetyltransferase 10 (NAA10), stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, further contributing to ferroptosis. The RGMB-AS1-HMOX1 and RGMB-AS1-NAA10 axes synergistically inhibited NSCLC growth both and . Clinically, low RGMB-AS1 expression was associated with advanced tumor stage and poor overall survival in NSCLC patients. Furthermore, adeno-associated virus-mediated RGMB-AS1 overexpression significantly suppressed tumor growth in mouse xenograft models. Our findings uncover a novel lncRNA-mediated regulatory mechanism of ferroptosis and highlight the potential of RGMB-AS1 as a prognostic biomarker and therapeutic target in NSCLC.

中文翻译：

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LncRNA RGMB-AS1抑制HMOX1泛素化和NAA10激活诱导非小细胞肺癌铁死亡

铁死亡是一种由过度脂质过氧化物积累引起的铁依赖性调节细胞死亡，已成为包括非小细胞肺癌（NSCLC）在内的各种癌症的有希望的治疗靶点。在这项研究中，我们发现长链非编码 RNA RGMB-AS1 是 NSCLC 铁死亡的关键调节因子。从机制上讲，RGMB-AS1 与血红素加氧酶 1 (HMOX1) 相互作用，并阻止其被 E3 连接酶 TRC8 泛素化，从而导致 HMOX1 稳定性增加和铁死亡增强。此外，RGMB-AS1 与 N-α-乙酰转移酶 10 (NAA10) 的 82-87 个氨基酸区域结合，刺激其乙酰转移酶活性并促进乙酰辅酶 A 转化为 HMG-CoA，进一步导致铁死亡。 RGMB-AS1-HMOX1 和 RGMB-AS1-NAA10 轴协同抑制 NSCLC 生长。临床上，RGMB-AS1 低表达与 NSCLC 患者的晚期肿瘤分期和较差的总生存率相关。此外，腺相关病毒介导的RGMB-AS1过表达显着抑制小鼠异种移植模型中的肿瘤生长。我们的研究结果揭示了一种新的 lncRNA 介导的铁死亡调节机制，并强调了 RGMB-AS1 作为 NSCLC 预后生物标志物和治疗靶点的潜力。