失巢凋亡是大多数脱离细胞常见的程序性死亡，但癌细胞可以获得失巢凋亡抵抗力，以促进其通过循环系统的远处转移。研究表明，自噬通量的增强是许多癌细胞在分离条件下存活的原因。靶向自噬进展的关键因素ATG4B可以在体外抑制癌症转移，但ATG4B缺陷小鼠易患多种严重疾病，这表明直接靶向ATG4B可能存在不受控制的副作用。在我们最近的研究中，我们证实 ATG4B 是胃癌 (GC) 细胞中的一种新型 RNA 结合蛋白。它与 circSPECC1 相互作用，从而促进 ATG4B 的液-液相分离和泛素化。此外，m6A 阅读器 ELAVL1 抑制 circSPECC1 的表达，从而增强 ATG4B 的表达和 GC 细胞的失巢凋亡抗性。此外，我们筛选出 FDA 批准的化合物洛匹那韦，以恢复 circSPECC1 丰度并抑制 GC 转移。总之，我们的研究确定了一条新的信号通路（ELAVL1-circSPECC1-ATG4B-autophagy）来促进GC细胞的失巢凋亡抵抗和转移，并筛选出具有临床应用潜力的化合物来阻断该通路，为预防GC细胞失巢凋亡提供了新的策略。 GC转移。版权所有：©2024Guo等人。

Anoikis is a common programmed death for most of detached cells, but cancer cells can obtain anoikis resistance to facilitate their distant metastasis through the circulation system. Researches have indicated that enhanced autophagic flux accounts for the survival of many cancer cells under detached conditions. Targeting ATG4B, the key factor of autophagy progress, can inhibit cancer metastasis in vitro, but ATG4B-deficient mice are susceptible to many serious diseases, which indicates the potential uncontrolled side effects of direct targeting of ATG4B. In our recent research, we confirmed that ATG4B is a novel RNA binding protein in the gastric cancer (GC) cell. It interacts with circSPECC1 which consequently facilitates the liquid-liquid phase separation and ubiquitination of ATG4B. Additionally, the m6A reader ELAVL1 inhibits the expression of circSPECC1 to enhance the expression of ATG4B and anoikis resistance of GC cells. Further, we screened out an FDA-approved compound, lopinavir, to restore circSPECC1 abundance and suppress GC metastasis. In conclusion, our research identified a novel signal pathway (ELAVL1-circSPECC1-ATG4B-autophagy) to facilitate anoikis resistance and metastasis of GC cells and screened out a compound with clinical application potential to block this pathway, providing a novel strategy for the prevention of GC metastasis.Copyright: © 2024 Guo et al.