凋亡途径一直被视为维持组织和器官稳态的关键因素。细胞死亡信号的过度激活或抵抗确实可能是几种疾病机制的罪魁祸首，包括恶性肿瘤和慢性退行性疾病。因此，定位凋亡因子在科学界获得了越来越多的关注，新的策略出现旨在有选择地阻止或刺激细胞死亡信号。这也适用于TMEM219死亡受体，它由循环配体胰岛素样生长因子结合蛋白3（IGFBP3）激活，并诱导靶细胞的caspase-8依赖性凋亡。有趣的是，IGFBP3/TMEM219轴的刺激具有抗增殖作用，而阻断TMEM219有害信号可保护内分泌胰腺、肺和肠道TMEM219表达细胞免受损伤和死亡。在这里，我们总结了关于IGFBP3/TMEM219凋亡轴在疾病条件下的作用的最新报告，包括肠道疾病和糖尿病，并描述了在新兴的潜在临床应用中设计和测试新型TMEM219定位方法的进展。© 2023年作者。BioEssays由Wiley Periodicals LLC发表。

Apoptotic pathways have always been regarded as a key-player in preserving tissue and organ homeostasis. Excessive activation or resistance to activation of cell death signaling may indeed be responsible for several mechanisms of disease, including malignancy and chronic degenerative diseases. Therefore, targeting apoptotic factors gained more and more attention in the scientific community and novel strategies emerged aimed at selectively blocking or stimulating cell death signaling. This is also the case for the TMEM219 death receptor, which is activated by a circulating ligand, the Insulin-like growth factor binding protein 3 (IGFBP3) and induces a caspase-8-dependent apoptosis of the target cells. Interestingly, stimulation of the IGFBP3/TMEM219 axis exerts an anti-proliferative effect, while blockade of the TMEM219 deleterious signal protects TMEM219-expressing cells of the endocrine pancreas, lung, and intestine from damage and death. Here, we summarize the most updated reports on the role of the IGFBP3/TMEM219 apoptotic axis in disease conditions, including intestinal disorders and diabetes, and we describe the advancements in designing and testing novel TMEM219-based targeting approaches in emerging potential clinical applications.© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.