缺氧是肺鳞状细胞癌 (LUSC) 的常见特征，缺氧诱导因子 1 (HIF-1) 过度表达与 LUSC 不良的临床结果相关。 NADH 脱氢酶 1 α 亚复合物亚基 4 样 2 (NDUFA4L2) 是最近确定的 HIF-1 靶标，但其在 LUSC 中的作用仍不清楚。在此，研究了NDUFA4L2在LUSC中的表达和调控机制，并确定了NDUFA4L2对LUSC细胞氧化代谢和存活的影响。鉴定了靶向 NDUFA4L2 的潜在 microRNA，并检测了其对 LUSC 细胞的作用。我们发现 NDUFA4L2 在 LUSC 组织中过度表达，并且 NDUFA4L2 表达与较短的总生存期相关。 NDUFA4L2在缺氧条件下受到HIF-1α的调节，NDUFA4L2通过抑制LUSC细胞中线粒体复合物I的活性来减少线粒体活性氧（mitoROS）的产生。 NDUFA4L2 沉默可有效抑制 LUSC 细胞生长，并通过诱导 mitoROS 积累来增强细胞凋亡。此外，NDUFA4L2 是 miR-183-5p 的靶标，miR-183-5p 水平高的 LUSC 患者预后更好。 MiR-183-5p 通过在体外和体内负调节 NDUFA4L2 显着诱导 mitoROS 产生并抑制 LUSC 存活。我们的结果表明，HIF-1α 对 NDUFA4L2 的调节是缺氧下促进 LUSC 进展的重要机制。使用强制 miR-183-5p 表达进行 NDUFA4L2 抑制可能是 LUSC 治疗的有效策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Hypoxia is a common feature of lung squamous cell carcinoma (LUSC), and hypoxia-inducible factor-1 (HIF-1) overexpression is associated with poor clinical outcome in LUSC. NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) is a recently identified target of HIF-1, but its roles in LUSC remain unclear. Herein, the expression and regulatory mechanisms of NDUFA4L2 were investigated in LUSC, and the influences on LUSC cell oxidative metabolism and survival of NDUFA4L2 were determined. The potential microRNA targeting to NDUFA4L2 was identified and its roles on LUSC cell were detected. We found that NDUFA4L2 were overexpressed in LUSC tissues, and that NDUFA4L2 expression correlated with shorter overall survival. NDUFA4L2 was regulated by HIF-1α under hypoxia, and NDUFA4L2 decreased mitochondrial reactive oxygen species (mitoROS) production through inhibiting mitochondrial complex I activity in LUSC cells. NDUFA4L2 silencing effectively suppressed LUSC cell growth and enhanced apoptosis by inducing mitoROS accumulation. Additionally, NDUFA4L2 was a target for miR-183-5p, and LUSC patients with high miR-183-5p levels had better prognoses. MiR-183-5p significantly induced mitoROS production and suppressed LUSC survival through negatively regulating NDUFA4L2 in vitro and in vivo. Our results suggested that regulation of NDUFA4L2 by HIF-1α is an important mechanism promoting LUSC progression under hypoxia. NDUFA4L2 inhibition using enforced miR-183-5p expression might be an effective strategy for LUSC treatment.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.