铁代谢失调与恶性转化、癌症进展和治疗耐药有关。在这里，我们证明铁调节蛋白 2 (IRP2) 优先调节铁代谢并促进结直肠癌 (CRC) 中的肿瘤生长。使用 RNA 干扰和成簇规则间隔短回文重复序列 (CRISPR)-Cas9 方法生成 IRP2 敲低和敲除细胞， 分别。使用 CCK-8 测定和细胞计数技术评估细胞活力。此外，通过表面等离振子共振 (SPR) 和 RNA 免疫沉淀 (IP) 测定 IRP2 抑制。 IRP2的抑制作用也在类器官和小鼠异种移植模型中得到证实，为IRP2的作用提供了全面的验证。我们已经阐明了IRP2作为铁代谢的优先调节剂的作用，积极促进CRC内的肿瘤发生。患者样本中 IRP2 表达水平升高与总生存期缩短相关，从而增强了其作为预后生物标志物的潜在作用。 IRP2 的功能抑制导致肿瘤生长明显延迟。基于这一概念验证，我们开发了 IRP2 抑制剂，可显着降低 IRP2 表达并阻碍其与关键铁调节蛋白（如铁蛋白重链 1 (FTH1) 和转铁蛋白受体 (TFRC)）中铁反应元件的相互作用，最终铁耗竭和结直肠癌细胞增殖显着减少。此外，这些抑制剂被证明可以激活 AMPK-ULK1-Beclin1 信号级联，导致 CRC 模型中的细胞死亡。总的来说，这些发现凸显了靶向 IRP2 来利用 CRC 铁代谢破坏的治疗潜力，呈现出战略进展解决未满足临床需求的关键领域。© 2024。作者。

Dysregulation of iron metabolism is implicated in malignant transformation, cancer progression, and therapeutic resistance. Here, we demonstrate that iron regulatory protein 2 (IRP2) preferentially regulates iron metabolism and promotes tumor growth in colorectal cancer (CRC).IRP2 knockdown and knockout cells were generated using RNA interference and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 methodologies, respectively. Cell viability was evaluated using both CCK-8 assay and cell counting techniques. Furthermore, IRP2 inhibition was determined by surface plasmon resonance (SPR) and RNA immunoprecipitation (IP). The suppressive effects of IRP2 were also corroborated in both organoid and mouse xenograft models, providing a comprehensive validation of IRP2's role.We have elucidated the role of IRP2 as a preferential regulator of iron metabolism, actively promoting tumorigenesis within CRC. Elevated levels of IRP2 expression in patient samples are correlated with diminished overall survival, thereby reinforcing its potential role as a prognostic biomarker. The functional suppression of IRP2 resulted in a pronounced delay in tumor growth. Building on this proof of concept, we have developed IRP2 inhibitors that significantly reduce IRP2 expression and hinder its interaction with iron-responsive elements in key iron-regulating proteins, such as ferritin heavy chain 1 (FTH1) and transferrin receptor (TFRC), culminating in iron depletion and a marked reduction in CRC cell proliferation. Furthermore, these inhibitors are shown to activate the AMPK-ULK1-Beclin1 signaling cascade, leading to cell death in CRC models.Collectively, these findings highlight the therapeutic potential of targeting IRP2 to exploit the disruption of iron metabolism in CRC, presenting a strategic advancement in addressing a critical area of unmet clinical need.© 2024. The Author(s).