Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage

Cong Yan; Yongqing Ye; Nan Liu; Dongdong Zhang; Wenzhong Du; Ying Li; GuoFu Li; Chen Li; Jingwei Li; Shengji Ma; Zifeng Dai; ZiYu Xiong; Yuwen Wang; Chunyang Men; Rui Bi; Qianpeng Duan; Weishi Xu; Husilengtu; Yuan Cao; Jiapei Du; Changbin Shi

doi:10.1016/j.bbrc.2025.152241

Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage

Biochem Biophys Res Commun. 2025 Jun 24:777:152241. doi: 10.1016/j.bbrc.2025.152241. Online ahead of print.

Authors

Cong Yan¹, Yongqing Ye¹, Nan Liu¹, Dongdong Zhang², Wenzhong Du², Ying Li¹, GuoFu Li³, Chen Li², Jingwei Li², Shengji Ma², Zifeng Dai⁴, ZiYu Xiong¹, Yuwen Wang¹, Chunyang Men¹, Rui Bi¹, Qianpeng Duan¹, Weishi Xu², Husilengtu¹, Yuan Cao¹, Jiapei Du¹, Changbin Shi⁵

Affiliations

¹ Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; NHC Key Laboratory of Cell Transplantation, Harbin, Heilongjiang, China.
² Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
³ Department of Neurosurgery, Harbin Medical University Cancer Hospital, Heilongjiang, China.
⁴ First Affiliated Hospital of Ningbo University, Zhejiang, China.
⁵ Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: changbinshi@hotmail.com.

PMID: 40570636
DOI: 10.1016/j.bbrc.2025.152241

Abstract

Cerebral cavernous malformations (CCM) present prevalent vascular diseases of the central nervous system, which can result in hemorrhage and seizures. Metformin, a first-line antidiabetic with established safety profiles, demonstrates pleiotropic effects, including the inhibition of cellular proliferation, inflammation, and angiogenesis, all of which are implicated in the pathogenesis of CCM. However, the therapeutic benefits of metformin in the realm of CCM remain unclear. This study aims to investigate the effect of metformin on the growth of CCM lesions in Slco1c1 CreERT2; Pdcd10 ^fl/fl (Pdcd10^BECKO) mice. Super-resolution confocal microscopy and transmission electron microscopy (TEM) were employed to evaluate mitochondrial structure. The results showed that metformin administration significantly attenuated CCM lesion burden, reduced iron deposition, and decreased collagen accumulation in Pdcd10^BECKO mice. Metformin also normalized the defects from PDCD10 deficiency, including disruption of tight junctions and excessive proliferation of endothelial cells. Moreover, metformin significantly improved mitochondrial structural anomalies and dysfunction associated with PDCD10 deficiency, characterized by the presence of mitochondrial puncta and the loss of cristae, followed by impaired mitochondrial membrane potential and increased mitoROS in endothelial cells with the mutation. Metformin provided these beneficial effects by downregulating KLF4. In conclusion, these findings indicate that metformin suppresses the development of CCM in Pdcd10^BECKO mice by targeting KLF4-mediated mitochondrial damage, thereby providing promising prospects as a novel therapeutic approach for CCM.

Keywords: Cerebral cavernous malformation; KLF4; Metformin; Mitochondria.

Published by Elsevier Inc.