《生命科学》 2026, 38(8): 1446-1462

蛋白C的生物学功能与应用研究进展

徐亦舒¹ , 曾 艺^1,2,*

¹中国科学院分子细胞科学卓越创新中心，上海 200031 ²国科大杭州高等研究院生命与健康科学学院， 杭州 310024

摘　要：

蛋白C在20世纪60~70年代被发现并分离，其最经典的功能是在受体依赖的情况下，被活化并切割凝血因子起到抗凝血的作用。近30年来，蛋白C被发现除了抗凝血外，亦可以发挥包括抗炎、抗凋亡以及增强细胞屏障的细胞保护作用，同时也可以直接参与对天然免疫以及适应性免疫细胞的调控。近年来，蛋白C及工程化变体的研究主要集中在临床应用方面，在脓毒症、神经炎症、糖尿病临床前动物模型上都有良好的表现，目前在肌萎缩侧索硬化症、慢性创面等疾病上已成功进入临床试验阶段。值得注意的是，蛋白C受体在包括造血、乳腺、血管、胰岛等多个组织中也被鉴定为成体干细胞的标志物。蛋白C在这些干细胞上通过其受体也发挥着重要的功能。本文综述了蛋白C在多种成体干细胞中的作用，为未来联合蛋白C信号与干细胞再生医学相互结合的治疗方案提供理论支持。

通讯作者：曾 艺 , Email:yzeng@sibcb.ac.cn

Advances in the biological functions and clinical applications of protein C

XU Yi-Shu¹ , ZENG Arial Yi^1,2,*

¹CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China ²School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China

Abstract:

Protein C (PC) was originally identified as a vitamin K-dependent anticoagulant zymogen, whose activated form, activated protein C (APC), down-regulates coagulation by proteolytically inactivating coagulation factors Va and VIIIa. However, research over the past five decades has revealed that the PC pathway plays far broader roles beyond anticoagulation. Through its interaction with endothelial protein C receptor (PROCR, EPCR) and protease-activated receptors (PARs), APC exerts potent cytoprotective, antiinflammatory, anti-apoptotic, endothelial barrier-stabilizing and immunomodulatory functions in a variety of tissues. Preclinical investigations have consistently shown that APC treatment confers significant therapeutic benefit across a broad spectrum of disease models, including ischemic stroke, inflammatory tissue injury, neurodegenerative disorders, diabetes, and chronic or non-healing wounds. Meanwhile, engineered APC variants with markedly reduced anticoagulant activity but preserved cytoprotective properties, such as 3K3A-APC, have demonstrated promising therapeutic potential in preclinical disease models and early-phase clinical trials.  These findings highlight the PC pathway as an important molecular regulator positioned at the interface between coagulation, inflammation, immunity and tissue regeneration. The purpose of this review is to summarize current progress regarding the biological roles of PC/APC and PROCR in adult stem cells, and to discuss the implications of these findings for regenerative medicine and disease therapy. Recent work has identified PROCR as a functional marker for multiple adult stem cell types, including hematopoietic, epidermal, vascular, mammary gland and pancreatic progenitor cells. PC/APC signaling has been shown to protect stem cells from apoptosis, modulate immune cell crosstalk, regulate stem-cell quiescence and homing, and contribute to maintenance of stem cell  niches. On the basis of current evidence, we propose that the PC-PROCR axis represents an emerging regulatory hub for stem cell biology and tissue protection. Future work should focus on clarifying the role of PC/APC in disease-altered stem-cell  microenvironments, and optimizing PC-based targeted therapeutics with minimal bleeding risk. Integration of stem cell-based  therapies and PC signaling may provide novel strategies for the treatment of inflammatory tissue injury, autoimmune diseases and degenerative diseases. Overall, the expanding understanding of the PC pathway not only revises its classical role in hemostasis, but also positions it as a promising target for next generation regenerative and immunomodulatory interventions.

Communication Author：ZENG Arial Yi , Email:yzeng@sibcb.ac.cn