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<p>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 <i>dipeptidyl peptidase-4 (DPP4)</i> 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.</p> Graphical Abstract <p></p>

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Targeting the non-enzymatic function of DPP4 via a nanobody inhibits cerebral cavernous malformation progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Chunyang Men,
  • Ziyu Xiong,
  • Qianpeng Duan,
  • Jiaxin Cheng,
  • Xiqing Luo,
  • Bao Yang,
  • Ying Li,
  • Cong Yan,
  • Yuwen Wang,
  • Yongqing Ye,
  • Rui Bi,
  • Zifeng Dai,
  • Silengtu Hu,
  • Xia Zhao,
  • Wenzhong Du,
  • Dongdong Zhang,
  • Changbin Shi

摘要

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.

Graphical Abstract