Brain Network Disorders review highlights role of JAK2 pathway in worsening ischemic stroke outcomes

Ischemic stroke is a major cause of death and disability, caused by a sudden loss of oxygen supply to the brain due to blocked blood vessels. Recanalization treatments such as intravenous thrombolysis and endovascular thrombectomy are commonly used to restore blood flow. However, more than half of treated patients still experience significant neurological impairment, suggesting that other damaging biological processes persist after treatment.

One such process is neuroinflammation—a prolonged immune response in the brain that begins within minutes of ischemia. Microglia and astrocytes become activated, releasing pro-inflammatory cytokines, increasing oxidative stress, disrupting the blood-brain barrier, and promoting brain edema. This inflammation worsens brain injury and interferes with recovery. Among the key drivers of this inflammation is the Janus kinase 2 (JAK2) pathway and its downstream partner, signal transducer and activator of transcription 3 (STAT3). Together, the JAK2-STAT3 axis plays a central role in amplifying the immune response and contributing to further damage in the brain. Although many studies have explored this pathway, a comprehensive overview has been lacking.

To address this gap, a team of researchers led by Professor Zhifeng Qi from Xuanwu Hospital, Capital Medical University, Beijing, in collaboration with Professor Ke Jian Liu from Stony Brook University, New York, conducted a detailed review of the JAK2-STAT3 pathway’s role in stroke. Their work was published in Volume 1, Issue 2 of the journal Brain Network Disorders and made available online on January 21, 2025.

In this review, the authors describe how the JAK2-STAT3 pathway contributes to inflammation and injury in different brain cell types following ischemic stroke. They explain that microglia—the brain’s resident immune cells—can adopt either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype after stroke. The JAK2 pathway promotes the M1 state, which leads to greater tissue damage and impaired axonal repair. In contrast, blocking JAK2 activity encourages M2 polarization, reduces cell death, and promotes neurogenesis.

“JAK2 signaling plays a damaging role in stroke-induced inflammation by amplifying multiple pathological cascades,” says Prof. Qi. “Targeting this pathway offers a promising therapeutic route, especially for patients who respond poorly to reperfusion therapies alone.”

Astrocytes, another key brain cell type, also show sustained STAT3 activation after stroke. This contributes to the formation of glial scars and the release of pro-inflammatory cytokines. Overactivation of the JAK/STAT pathway in astrocytes has been linked to long-term structural and functional damage in the brain. In neurons, JAK2 signaling is associated with cell death and cognitive decline, particularly in the ischemic striatum. Meanwhile, endothelial cells lining blood vessels in the affected area release reactive oxygen species and inflammatory cytokines that further damage the blood-brain barrier and promote vascular inflammation.

The body does have natural mechanisms to limit JAK2 activity, including protein tyrosine phosphatases (PTPs), SOCS proteins, and other inhibitors. However, these controls often fail during acute ischemia. Meanwhile, amplifiers such as HMGB1 and NLRP3 worsen inflammation by triggering pyroptosis, edema, and tissue breakdown.

The review also evaluates several JAK2 inhibitors as potential stroke treatments. Tyrphostin AG490 has shown promise in reducing brain swelling and neuronal death in preclinical models. Ruxolitinib, currently used for blood cancers, suppresses cytokine storms and dampens inflammation in stroke-affected brains. Natural compounds such as genistein, Atractylenolide III, and nicotiflorin have also been found to reduce JAK2/STAT3 activity and protect brain cells. While these results are promising, the authors note that none of these inhibitors have been tested in stroke patients.

“Combining recanalization with targeted modulation of the JAK2-mediated inflammatory response may offer a much-needed therapeutic advance,” concludes Prof. Qi. “Our goal is to bridge the gap between vessel reopening and true neurological recovery.”

***

Reference
DOI: 10.1016/j.bnd.2024.09.001

Funding information
This work was supported in part by grants from the Beijing Municipal Natural Science Foundation (No. 7222080) and the National Natural Science Foundation of China (No. 82271308).