Targeted protein degradation has become a notable drug development strategy, but its application has been limited by the dependence on protein-based chimeras with restricted genetic manipulation capabilities. The use of long non-coding RNAs (lncRNAs) has emerged as a viable alternative, offering interactions with cellular proteins to modulate pathways and enhance degradation capabilities. Here we introduce a strategy employing artificial lncRNAs (alncRNAs) for precise targeted protein degradation. By integrating RNA aptamers and sequences from the lncRNA HOTAIR, our alncRNAs specifically target and facilitate the ubiquitination and degradation of oncogenic transcription factors and tumor-related proteins, such as c-MYC, NF-κB, ETS-1, KRAS and EGFR. These alncRNAs show potential in reducing malignant phenotypes in cells, both in vitro and in vivo, offering advantages in efficiency, adaptability and versatility. This research enhances knowledge of lncRNA-driven protein degradation and presents an effective method for targeted therapies.

靶向蛋白质降解已成为一种值得注意的药物开发策略，但其应用因依赖于遗传操作能力有限的基于蛋白质的嵌合体而受到限制。长非编码 RNA (lncRNA) 的使用已成为一种可行的替代方案，它可以与细胞蛋白质相互作用来调节途径并增强降解能力。在这里，我们介绍了一种利用人工 lncRNA (alncRNA) 进行精确靶向蛋白质降解的策略。通过整合来自 lncRNA HOTAIR 的 RNA 适体和序列，我们的 ancRNA 特异性靶向并促进致癌转录因子和肿瘤相关蛋白（如 c-MYC、NF-κB、ETS-1、KRAS 和 EGFR）的泛素化和降解。这些alncRNA在体外和体内均显示出减少细胞恶性表型的潜力，在效率、适应性和多功能性方面具有优势。这项研究增强了对 lncRNA 驱动的蛋白质降解的认识，并为靶向治疗提供了一种有效的方法。