CRC的发病率逐年增加，已经成为全球公共卫生的重要负担。天然药物黄樟素（BBR）已经展现出在预防CRC方面的潜力，而IGF2 mRNA结合蛋白3（IGF2BP3）可能是BBR的一个靶标。本研究旨在探讨BBR作用于IGF2BP3来改善CRC的机制。结果显示，IGF2BP3在CRC的发展中起着重要作用。BBR下调了IGF2BP3的表达，并抑制了小鼠中的CRC生长。细胞热力学稳定性分析（CETSA）和药物亲和力响应靶标稳定性（DARTS）分析均表明BBR可能与IGF2BP3结合。BBR可能会诱导IGF2BP3结构发生变化，并降低其在细胞质中的蛋白稳定性。免疫共沉淀（Co-IP）的结果表明，BBR通过三方结构域含蛋白21（TRIM21）促进了IGF2BP3的泛素化。通过RNA结合蛋白免疫沉淀（RIP）试验发现，BBR抑制了IGF2BP3对CDK4 / CCND1 mRNA的稳定作用，并促进了CRC细胞的G1 / S期阻滞。体外和体内过表达IGF2BP3减弱了BBR对CRC生长的抑制作用。本研究展示了BBR针对IGF2BP3改善CRC的潜力，并为临床治疗CRC提供了新的策略，以及基于IGF2BP3和TRIM21的新型抗癌药物设计。Copyright © 2023.由Elsevier B.V.出版。

The increasing incidence of colorectal cancer (CRC) has become a major global public health burden. The natural drug Berberine (BBR) has shown potential in preventing CRC, and IGF2 mRNA binding protein 3 (IGF2BP3) may be a target of BBR. This study aims to investigate the mechanisms of BBR acting on IGF2BP3 to improve CRC. The results showed that IGF2BP3 played an important role in the development of CRC. BBR down-regulated IGF2BP3 expression and inhibited CRC growth in mice. Cell thermodynamic stability analysis (CETSA) and drug affinity responsive target stability (DARTS) analysis showed BBR may bind to IGF2BP3. BBR may induce structural changes in IGF2BP3 and decrease its protein stability in cytoplasm. The results from Co-Immunoprecipitation (Co-IP) suggested that BBR promoted the ubiquitination of IGF2BP3 by tripartite motif-containing protein 21 (TRIM21). Through RNA binding protein Immunoprecipitation (RIP) assay, it was found BBR inhibited the stabilization of CDK4/CCND1 mRNA by IGF2BP3 and promoted G1/S phase arrest in CRC cells. Overexpression of IGF2BP3 in vitro and in vivo attenuated the inhibition of CRC growth by BBR. This work demonstrated the potential of BBR targeting to IGF2BP3 in improving CRC and provided a new strategy for clinical treatment on CRC as well as novel anticancer drug design based on IGF2BP3 and TRIM21.Copyright © 2023. Published by Elsevier B.V.