二肽基肽酶4的多维生物学功能与靶向干预策略研究进展

Research progress on multidimensional biological functions and targeted intervention strategies of dipeptidyl peptidase 4

摘要:

二肽基肽酶4 (dipeptidyl peptidase 4, DPP4)作为一种广泛表达于多种细胞类型的膜结合蛋白，其主要功能是催化多肽底物N端X-Pro或X-Ala二肽的切除。在糖代谢调控中，DPP4通过降解肠促胰岛素参与血糖稳态的维持，因而成为治疗2型糖尿病的重要靶点。此外，DPP4在纤维化、炎症及肿瘤等病理过程中也显示出作为生物标志物和干预靶点的潜力。在干预策略方面，除传统小分子抑制剂外，DPP4抑制肽在体外实验中表现出显著的酶活抑制能力，提示其在控制高血糖方面的潜在应用价值。同时，针对DPP4的特异性抗体药物的研发也取得进展，为DPP4相关疾病的诊断与治疗提供了新方向。本文系统综述了从DPP4的经典酶学功能与升糖机制，到其在纤维化、炎症及肿瘤等疾病中的新型病理功能，进而讨论了涵盖小分子药物、抑制肽与抗体在内的多元化干预策略的最新研究进展，深化了对DPP4多维生物学功能及其疾病关联性的整体认识，并为DPP4靶向干预策略的优化与新型治疗手段的开发提供了理论依据。

Abstract:

Dipeptidyl peptidase 4 (DPP4) is a membrane-anchored protein ubiquitously expressed across various cell types, primarily responsible for cleaving N-terminal X-Pro or X-Ala dipeptides from polypeptides. It plays a crucial role in glucose metabolism by degrading incretin hormones, thereby regulating blood glucose homeostasis and establishing itself as a key therapeutic target for type 2 diabetes mellitus. In addition, DPP4 has emerged as a potential biomarker and intervention target in pathologies such as fibrosis, inflammation, and cancer. In terms of therapeutic strategies, in addition to conventional small-molecule inhibitors, DPP4-inhibitory peptides have shown significant efficacy in vitro, underscoring their potential for the control of high blood glucose. Advancements in the development of DPP4-specific antibodies are creating new opportunities for diagnosing and treating DPP4-related diseases. This review systematically delineates the established enzymatic functions and blood glucose-rising mechanisms of DPP4, its novel pathological roles in fibrotic, inflammatory, and oncological processes, and discusses recent progress in diverse intervention strategies, including small molecules, inhibitory peptides, and antibodies. It helps deepen the overall understanding of the multifaceted biological functions of DPP4 and its associations with disease, and provides a theoretical basis for optimizing DPP4-targeted therapeutic strategies and developing novel treatment approaches.