Chen Can, Liu Mei, Tao Xiang
Institute of Liver and Gastrointestinal Diseases, Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Biomedicines. 2025 May 23;13(6):1285. doi: 10.3390/biomedicines13061285.
Phosphodiesterase 4 (PDE4) serves as a crucial regulator of cyclic adenosine monophosphate (cAMP) signaling and has been identified as a significant therapeutic target for inflammatory and metabolic disorders impacting the gastrointestinal (GI) tract and liver. Although pan-PDE4 inhibitors hold therapeutic promise, their clinical use has been constrained by dose-dependent adverse effects. Recent progress in the development of isoform-specific PDE4 inhibitors, such as those selective for PDE4B/D, alongside targeted delivery systems like liver-targeting nanoparticles and probiotic-derived vesicles, is reshaping the therapeutic landscape. This review consolidates the latest insights into PDE4 biology, highlighting how the structural characterization of isoforms informs drug design. We conduct a critical evaluation of preclinical and clinical data across various diseases, including inflammatory bowel diseases (IBDs), alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, and digestive tract tumors, with an emphasis on mechanisms extending beyond cAMP modulation, such as microbiota remodeling and immune reprogramming. Additionally, we address challenges in clinical translation, including biomarker discovery and the heterogeneity of trial outcomes, and propose a roadmap for future research directions.
磷酸二酯酶4（PDE4）是环磷酸腺苷（cAMP）信号传导的关键调节因子，已被确定为影响胃肠道（GI）和肝脏的炎症及代谢紊乱的重要治疗靶点。尽管泛PDE4抑制剂具有治疗前景，但其临床应用受到剂量依赖性不良反应的限制。亚型特异性PDE4抑制剂（如对PDE4B/D具有选择性的抑制剂）以及肝脏靶向纳米颗粒和益生菌衍生囊泡等靶向递送系统的最新进展正在重塑治疗格局。本综述整合了对PDE4生物学的最新见解，强调了亚型的结构特征如何为药物设计提供信息。我们对包括炎症性肠病（IBD）、酒精性肝病、非酒精性脂肪性肝病（NAFLD）、肝纤维化和消化道肿瘤在内的各种疾病的临床前和临床数据进行了批判性评估，重点关注超出cAMP调节的机制，如微生物群重塑和免疫重编程。此外，我们还讨论了临床转化中的挑战，包括生物标志物发现和试验结果的异质性，并提出了未来研究方向的路线图。
