1. Academic Validation
  2. The SGLT2 inhibitor dapagliflozin suppresses endothelial cell pyroptosis mediated by the NF-κB/NLRP3 pathway through downregulation of CTSB

The SGLT2 inhibitor dapagliflozin suppresses endothelial cell pyroptosis mediated by the NF-κB/NLRP3 pathway through downregulation of CTSB

  • Biochem Pharmacol. 2025 Mar 7:236:116857. doi: 10.1016/j.bcp.2025.116857.
Quanwei Zhao 1 Hui Li 2 Danan Liu 3 Bo Zhou 4 Caiwei Gong 5 Long Chen 5 Fujun Liao 5
Affiliations

Affiliations

  • 1 Department of Cardiovascular, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China; Foshan Fusun Chancheng Hospital, Foshan, Guangdong 528000, China.
  • 2 The First People's Hospital of Qujing City, Qujing, Yunnan 655000, China; Kunming Medical University Affiliated Qujing Hospital, Qujing, Yunnan 655000, China.
  • 3 Department of Cardiovascular, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China; The Institute of Medical Science of Guizhou Medical University, Guiyang, Guizhou 550004, China. Electronic address: liudanan@gmc.edu.cn.
  • 4 Department of Cardiovascular, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China; Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China.
  • 5 Department of Cardiovascular, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China.
Abstract

Atherosclerosis (AS) is a chronic inflammatory disease, and pyroptosis-a recently discovered pro-inflammatory programmed cell death process-can exacerbate these inflammatory responses. Vascular endothelial cell Pyroptosis contributes to AS progression. Cathepsin B (CTSB) is a crucial member of the cysteine protease family found in lysosomes. However, its exact role in vascular endothelial cell Pyroptosis remains unclear. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, inhibits Pyroptosis and alleviates AS independent of its hypoglycemic effect. This study utilized oxidized low-density lipoprotein (ox-LDL) to induce Pyroptosis in human umbilical vein endothelial cells (HUVECs) and investigated the effect of this process. The study revealed that ox-LDL induced HUVEC Pyroptosis in a concentration-dependent manner, resulting in Na+ and CA2+ overload, lysosomal damage, and increased CTSB release into the cytosol. Lentiviral vectors were used to overexpress or silence CTSB; subsequent analysis revealed that CTSB promotes NLRP3-mediated Pyroptosis through nuclear factor κB (NF-κB) activation. Finally, we found that DAPA attenuated HUVEC Pyroptosis by inhibiting the NF-κB/NLRP3 pathway and decreasing the expression of CTSB. This effect may be attributed to its ability to alleviate lysosomal damage caused by Na+-Ca2+ overload, thereby reducing CTSB release into the cytosol.

Keywords

Cathepsin B; Dapagliflozin; Human umbilical vein endothelial cells; Nuclear Factor κB; Pyroptosis.

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