Regenerating pancreatic β-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of β-cell regeneration, but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction we genetically validated in vivo. CID661578 increased β-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding eIF4G in the translation initiation complex at the mRNA cap. Unexpectedly, this blocking activity augmented eIF4E phosphorylation depending on MNK1 and bolstered the interaction between eIF4E and eIF4G, which is necessary for both hypertranslation and β-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in β-cell regeneration, a role that warrants further investigation in diabetes.

再生胰腺 β 细胞是一种潜在的糖尿病治疗方法。我们之前将小分子 CID661578 鉴定为 β 细胞再生的有效诱导剂，但其作用靶点和作用机制仍然未知。我们现在筛选了 2.57 亿个酵母克隆，并确定 CID661578 靶向 MAP 激酶相互作用的丝氨酸/苏氨酸激酶 2 (MNK2)，这是一种我们在体内进行了基因验证的相互作用。CID661578 增加了斑马鱼、新生猪胰岛聚集体和人类胰腺导管类器官中导管细胞的 β 细胞新生。从机制上讲，我们发现 CID661578 通过阻止 MNK2 在 mRNA 帽的翻译起始复合物中结合 eIF4G 来促进蛋白质合成和再生。不料，这种阻断活性增强了依赖于 MNK1 的 eIF4E 磷酸化，并增强了 eIF4E 和 eIF4G 之间的相互作用，这对于超翻译和 β 细胞再生都是必需的。综上所述，我们的研究结果证明了 MNK2 控制的翻译在 β 细胞再生中的靶向作用，这一作用值得在糖尿病中进一步研究。