For ischaemic stroke patients, although revascularisation therapies such as intravenous thrombolysis and mechanical thrombectomy restore blood flow, many of them still experience secondary haemorrhage, blood-brain barrier (BBB) leakage, and poor neurological recovery. Biological drivers of these post-reperfusion injuries remain unclear.

In a study published in European Heart Journal on December 26, a research team from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences, along with collaborators, have uncovered a previously unknown neuronal signaling mechanism that amplifies brain injury after ischaemic stroke.

Researchers found that after cerebral ischaemia, a subset of stressed neurons released high levels of Dickkopf-related protein 2 (DKK2) which suppressed the canonical Wnt/β-catenin pathway essential for neuronal survival and BBB integrity. The suppression triggered a cascade of events that exacerbated neuronal injury, compromised BBB, increased haemorrhagic transformation risk, and ultimately enlarged the infarct area.

By integrating genetic manipulation, viral tools and antibody-based inhibition, researchers showed that reducing DKK2 activity significantly decreased infarct size, preserved BBB structure, and improved neurological outcomes in mouse models of ischaemic stroke. 

Conversely, they showed that elevating DKK2 levels worsened brain injury, confirming its causal role. Moreover, they identified retinoid X receptor-α (RXRα) as an upstream regulator responsible for driving neuronal DKK2 expression under ischaemia-reperfusion conditions.

Researchers analyzed serum samples from patients undergoing mechanical thrombectomy. They found that higher DKK2 concentrations were associated with larger infarcts, intracranial haemorrhage, and poorer 90-day functional outcomes, which provides clinical support for mechanistic findings observed in experimental models.

This study reveals a complete mechanistic link between neuronal activation, Wnt pathway inhibition and BBB disruption, and identifies DKK2 as a promising target for therapeutic intervention. Neutralizing DKK2 may offer a strategy to protect the neurovascular unit and reduce complications in patients who miss the narrow time window for conventional revascularisation therapies.