Ischaemic stroke remains a leading cause of death and disability worldwide. Although revascularisation therapies – such as intravenous thrombolysis and mechanical thrombectomy – can restore blood flow, many patients continue to experience secondary brain injury, including blood–brain barrier (BBB) disruption, intracranial haemorrhage, and poor neurological recovery. The molecular mechanisms underlying this post-reperfusion injury have remained largely unclear.

A research team from the Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, has uncovered a neuron-derived signaling mechanism that critically amplifies neurovascular damage following cerebral ischaemia. The findings have been published in European Heart Journal, one of the leading journals in cardiovascular research.

The study demonstrates that after cerebral ischaemia, a subset of stressed neurons releases high levels of Dickkopf-related protein 2 (DKK2). Rather than providing protection, DKK2 suppresses the canonical Wnt/β-catenin pathway, which is essential for neuronal survival and blood–brain barrier (BBB) integrity. This suppression triggers a cascade of events that exacerbates neuronal injury, compromises the BBB, increases the risk of haemorrhagic transformation and ultimately enlarges the infarct area.

Using a combination of genetic manipulation, viral tools and antibody-based inhibition, the researchers show that reducing DKK2 activity significantly decreases infarct size, preserves BBB structure and improves neurological outcomes in mouse models of ischaemic stroke. Conversely, elevating DKK2 levels worsens brain injury, confirming its causal role.

The team also identified retinoid X receptor-α (RXRα) as an upstream regulator responsible for driving neuronal DKK2 expression under ischaemia–reperfusion conditions.

To explore its significance in humans, the researchers analyzed serum samples from patients undergoing mechanical thrombectomy. Higher DKK2 concentrations were associated with larger infarcts, intracranial haemorrhage and poorer 90-day functional outcomes, providing clinical support for the mechanistic findings observed in experimental models.

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