The glucocorticoid receptor (GR) is a major nuclear receptor (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite the effectiveness of GR ligands, their systemic action triggers a plethora of side effects, limiting long-term use. Here, we discuss new concepts of and insights into GR mechanisms of action to assist in the identification of routes toward enhanced therapeutic benefits. We zoom in on the communication between different GR domains and how this is influenced by different ligands. We detail findings on the interaction between GR and chromatin, and highlight how condensate formation and coregulator confinement can perturb GR transcriptional responses. Last, we discuss the potential of novel ligands and the therapeutic exploitation of crosstalk with other NRs.

中文翻译：

---

糖皮质激素受体信号传导：复杂性和治疗机会

糖皮质激素受体 (GR) 是治疗炎症性疾病和多种癌症的主要核受体 (NR) 药物靶点。尽管 GR 配体有效，但其全身作用会引发大量副作用，限制了长期使用。在这里，我们讨论 GR 作用机制的新概念和见解，以帮助确定增强治疗效果的途径。我们重点研究不同 GR 结构域之间的通讯以及不同配体对其的影响。我们详细介绍了 GR 和染色质之间相互作用的发现，并强调了冷凝物形成和共调节器限制如何扰乱 GR 转录反应。最后，我们讨论了新型配体的潜力以及与其他 NR 串扰的治疗利用。