Lung cancer is a common malignancy characterized by ferroptosis, an iron‐dependent form of cell death caused by excessive lipid peroxidation. The disruption of the ubiquitination system plays a crucial role in tumor development and spread. In recent years, there has been increasing interest in utilizing ferroptosis for lung cancer treatment; however, the precise mechanism of how ubiquitination modulates ferroptosis remains unclear. We used databases to analyze STUB1 expression patterns in lung cancer tissues compared to normal tissues and performed immunohistochemistry. The functional role of STUB1 was investigated through gain‐of‐function and loss‐of‐function experiments both in vitro and in vivo. Malondialdehyde levels, Fe2+ content, and cell viability assays were employed to evaluate ferroptosis status. Downstream targets of STUB1 were identified through screening and validated using immunoprecipitation and ubiquitination assays. Our findings demonstrate that STUB1 is downregulated in lung cancer cells and functions as an inhibitor of their growth and metastasis both in vitro and in vivo while promoting ferroptosis. Mechanistically, STUB1 induces ferroptosis through E3 ligase‐dependent degradation of the ferroptosis suppressor HSPB1. Furthermore, our study elucidated the specific types and sites of modification on HSPB1 mediated by STUB1. This research establishes STUB1 as a tumor suppressor influencing proliferation of lung cancer cells as well as the epithelial‐mesenchymal transition process associated with it. Importantly, our work highlights the role of STUB1 in ubiquitination‐mediated degradation of HSPB1, providing insights for potential treatments for lung cancer.

中文翻译：

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STUB1促进HSPB1降解并诱导肺癌细胞铁死亡

肺癌是一种常见的恶性肿瘤，其特征是铁死亡，这是一种由过度脂质过氧化引起的铁依赖性细胞死亡形式。泛素化系统的破坏在肿瘤的发展和扩散中起着至关重要的作用。近年来，人们越来越关注利用铁死亡来治疗肺癌。然而，泛素化如何调节铁死亡的确切机制仍不清楚。我们使用数据库分析了肺癌组织与正常组织中 STUB1 的表达模式，并进行了免疫组织化学分析。通过体外和体内功能获得和功能丧失实验研究了 STUB1 的功能作用。丙二醛含量，Fe2+采用含量和细胞活力测定来评估铁死亡状态。 STUB1 的下游靶标是通过筛选确定的，并使用免疫沉淀和泛素化测定进行验证。我们的研究结果表明，STUB1 在肺癌细胞中下调，并在体外和体内作为其生长和转移的抑制剂，同时促进铁死亡。从机制上讲，STUB1 通过铁死亡抑制因子 HSPB1 的 E3 连接酶依赖性降解来诱导铁死亡。此外，我们的研究阐明了 STUB1 介导的 HSPB1 修饰的具体类型和位点。这项研究确立了 STUB1 作为一种肿瘤抑制因子，影响肺癌细胞的增殖以及与之相关的上皮间质转化过程。重要的是，我们的工作强调了 STUB1 在泛素化介导的 HSPB1 降解中的作用，为肺癌的潜在治疗提供了见解。