Targeting the non-enzymatic function of DPP4 via a nanobody inhibits cerebral cavernous malformation progression.
5 affiliations
- 1Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang province, China.
- 2NHC Key Laboratory of Cell Transplantation, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
- 3Department of Critical Care Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
- 4First Affiliated Hospital of Ningbo University, Zhejiang, China.
- 5Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang province, China. [email protected].
Abstract
Cerebral cavernous malformations (CCMs) cause hemorrhagic stroke and lack effective pharmacological therapies. Although multiple extracellular stimuli contribute to CCM progression, how these signals are integrated across the plasma membrane remains unclear. Through transcriptomic analysis, we identified dipeptidyl peptidase-4 (DPP4) as a hub gene that may link extracellular stimuli to endothelial dysfunction, with elevated expression in CCM lesions. DPP4 is a type Ⅱ transmembrane glycoprotein that possesses both enzymatic and non-enzymatic functions. DPP4 knockdown reverses endothelial dysfunction in vitro and suppresses CCM progression in vivo. Single-cell transcriptomic analysis further reveals that DPP4 promotes pro-angiogenic signaling and is associated with caveolin-1 (CAV1). Mechanistically, our data suggest that DPP4 promotes CCM pathogenesis via a non-enzymatic interaction with CAV1, largely independent of its canonical enzymatic activity. This interaction promotes CAV1 phosphorylation and downstream FAK signaling activation. To selectively target the predicted interface epitope on DPP4, we developed a structure-guided nanobody (DC499-mFc) and functionally disrupted the DPP4-CAV1 interaction. This nanobody-based strategy effectively attenuates CCM progression in vivo. Collectively, these findings suggest that DPP4 contributes to CCM progression and point to nanobody‑based disruption of the non‑enzymatic DPP4-CAV1 interaction as a potential therapeutic strategy for CCM.
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BibTeX
@article{men2026targeting,
title = {{Targeting the non-enzymatic function of DPP4 via a nanobody inhibits cerebral cavernous malformation progression.}},
author = {Chunyang Men and Ziyu Xiong and Qianpeng Duan and Jiaxin Cheng and Xiqing Luo and Bao Yang and Ying Li and Cong Yan and Yuwen Wang and Yongqing Ye and Rui Bi and Zifeng Dai and Silengtu Hu and Xia Zhao and Wenzhong Du and Dongdong Zhang and Changbin Shi},
journal = {Journal of nanobiotechnology},
year = {2026},
month = aug,
doi = {10.1186/s12951-026-04898-x},
url = {https://europepmc.org/article/MED/42968142},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting the non-enzymatic function of DPP4 via a nanobody inhibits cerebral cavernous malformation progression.
AU - Chunyang Men
AU - Ziyu Xiong
AU - Qianpeng Duan
AU - Jiaxin Cheng
AU - Xiqing Luo
AU - Bao Yang
AU - Ying Li
AU - Cong Yan
AU - Yuwen Wang
AU - Yongqing Ye
AU - Rui Bi
AU - Zifeng Dai
AU - Silengtu Hu
AU - Xia Zhao
AU - Wenzhong Du
AU - Dongdong Zhang
AU - Changbin Shi
PY - 2026
DA - 2026/08/05
JO - Journal of nanobiotechnology
DO - 10.1186/s12951-026-04898-x
UR - https://europepmc.org/article/MED/42968142
AB - Cerebral cavernous malformations (CCMs) cause hemorrhagic stroke and lack effective pharmacological therapies. Although multiple extracellular stimuli contribute to CCM progression, how these signals are integrated across the plasma membrane remains unclear. Through transcriptomic analysis, we identified dipeptidyl peptidase-4 (DPP4) as a hub gene that may link extracellular stimuli to endothelial dysfunction, with elevated expression in CCM lesions. DPP4 is a type Ⅱ transmembrane glycoprotein that possesses both enzymatic and non-enzymatic functions. DPP4 knockdown reverses endothelial dysfunction in vitro and suppresses CCM progression in vivo. Single-cell transcriptomic analysis further reveals that DPP4 promotes pro-angiogenic signaling and is associated with caveolin-1 (CAV1). Mechanistically, our data suggest that DPP4 promotes CCM pathogenesis via a non-enzymatic interaction with CAV1, largely independent of its canonical enzymatic activity. This interaction promotes CAV1 phosphorylation and downstream FAK signaling activation. To selectively target the predicted interface epitope on DPP4, we developed a structure-guided nanobody (DC499-mFc) and functionally disrupted the DPP4-CAV1 interaction. This nanobody-based strategy effectively attenuates CCM progression in vivo. Collectively, these findings suggest that DPP4 contributes to CCM progression and point to nanobody‑based disruption of the non‑enzymatic DPP4-CAV1 interaction as a potential therapeutic strategy for CCM.
SN - 1477-3155
ER -