Role of the WNT signalling pathway in physiological and pathological blood-brain barrier

The blood-brain barrier (BBB) is essential for maintaining central nervous system (CNS) homeostasis and protecting neural tissue. The wingless-type MMTV integration site family (WNT) signalling pathway has emerged as a key regulator of BBB development, maintenance, and repair. Dysregulation of this pathway is implicated in BBB dysfunction associated with various neurological disorders.

We conducted a comprehensive review of recent literature integrating data from animal models, human induced pluripotent stem cell (iPSC)-derived BBB systems, and disease-specific mechanistic studies. The role of canonical and non-canonical WNT signalling in BBB formation, maturation, and pathological alteration was systematically analyzed.

WNT7a/b ligands activate β-catenin-dependent signalling to drive cerebral angiogenesis and BBB differentiation, with G protein‑coupled receptor 124 (GPR124), Reversion‑inducing cysteine‑rich protein with Kazal motifs (RECK), and SRY‑related HMG‑box transcription factor 17 (Sox17) identified as critical co-regulators. In the mature BBB, WNT activity is suppressed epigenetically to maintain barrier stability. In diseases such as ischaemic stroke, Alzheimer's disease, multiple sclerosis, and glioblastoma, WNT signalling is disrupted, leading to BBB breakdown. Pharmacological activation of WNT/β-catenin signalling (e.g. lithium, Glycogen synthase kinase 3β (GSK-3β) inhibitors and engineered WNT ligands) restores BBB integrity in preclinical models. Additionally, modulation of WNT signalling can enhance drug delivery across the BBB, offering therapeutic advantages in brain tumours and neurodegenerative diseases.

WNT signalling is a central molecular axis governing BBB integrity under both physiological and pathological conditions. Targeted modulation of this pathway represents a promising therapeutic strategy for restoring BBB function and improving CNS drug delivery. Further mechanistic and translational studies are warranted to advance clinical applications.