Table 2.

CCM-related signalling pathways

Pathway classification	Signalling pathways	Pathogenic mechanism	References
Core cellular signalling pathways associated with pathogenicity	MEKK3–KLF2/4 Signaling Axis	Loss of CCM proteins relieves inhibition of MAP3K3 (MEKK3), leading to persistent activation of downstream KLF2 and KLF4, transcription factors that drive a pathogenic endothelial program. It integrates hemodynamic and inflammatory signals and promotes cellular proliferation, migration, and lesion formation.	[8, 13, 34, 35, 40]
	RhoA–ROCK Signalling Dysregulation	The CCM protein complex normally inhibits the RhoA–ROCK pathway. Loss leads to ROCK overactivation, increased actomyosin contractility, cytoskeletal stress, and breakdown of endothelial junctions.	[42, 53]
	PI3K-mTOR	PI3K–AKT → mTOR activation promotes endothelial proliferation, survival, and lesion growth, and can synergise with MAP3K3 activation	[25, 35, 36, 41]
	MAP3K3–mTOR	MAP3K3–mTOR signalling constitutes a growth-permissive axis that converts endothelial genetic lesions into progressive CCM pathology.	[33, 36, 43]
	TGF-β/BMP/β-catenin	β-catenin proteins concentrate in the nucleus to drive the expression of dedifferentiation-related proteins, including stem cell/endMT markers, and to activate TGF-β/BMP signalling, promoting vascular pathology.	[42, 51, 52]
	Oxidative Stress Pathways	KRIT1 loss produces oxidative imbalance, and ROS overproduction may sensitize the endothelium to dysfunction	[31]
	Hypoxia-CX3CR1-CX3CL1	Persistent mild hypoxia influences cell-specific neuroinflammatory interactions through the CX3CR1-CX3CL1 signalling pathway, leading to CCM severity heterogeneity	[48]