The STING-GDF15-STAT3 signaling axis contributes to neuroinflammatory responses and secondary brain injury after ICH, and may represent a potential therapeutic target for hemorrhagic stroke.
STING expression was significantly increased in human and murine ICH tissues and was primarily localized to microglia.
Plasma STING levels were positively associated with disease severity in patients with ICH.
Inhibition or genetic deletion of STING reduced GDF15 expression, attenuated neuroinflammation, and alleviated brain injury after ICH.
STING activation with the agonist DMXAA worsened neuronal damage and neurological deficits after ICH.
In vitro STING activation in hemin-treated microglia enhanced GDF15 expression, STAT3 phosphorylation, oxidative stress, and inflammatory cytokine production.
Neutralization of GDF15 significantly ameliorated neuroinflammation, reduced brain edema, and improved behavioral impairments after ICH.
Intracerebroventricular administration of the anti-GDF15 monoclonal antibody ponsegromab markedly improved behavioral performance and attenuated secondary brain injury after ICH.
Transcriptomic profiling identified GDF15 as a key downstream effector of STING signaling in ICH.
This research suggests that a specific molecular signaling chain — involving proteins called STING, GDF15, and STAT3 — plays an important role in driving brain inflammation after a type of stroke called intracerebral hemorrhage (ICH), which occurs when blood leaks directly into brain tissue. The researchers found that STING levels are elevated in brain tissue from both human ICH patients and mice with ICH, and that STING is mainly found in microglia (the brain's immune cells). They also found that higher STING levels in the blood of ICH patients were linked to more severe disease, suggesting STING could potentially serve as a marker of how bad a patient's condition is. Using mouse models of ICH, the researchers showed that blocking or deleting STING reduced inflammation and brain damage, while activating STING made things worse. They traced the mechanism: STING activation in microglia increases a protein called GDF15, which then activates another protein called STAT3, promoting oxidative stress and the release of inflammatory molecules that damage brain tissue. Importantly, when they blocked GDF15 using a drug called ponsegromab — delivered directly into the brain — mice with ICH had less brain swelling, less inflammation, and better physical and behavioral performance. This research suggests that the STING-GDF15-STAT3 pathway is a potentially important contributor to the brain damage that follows ICH, and that targeting GDF15 — possibly using existing drugs like ponsegromab — could be a new therapeutic strategy for this devastating and currently hard-to-treat condition. Because ponsegromab is already a known antibody drug, these findings may have translational relevance, though further research in humans would be needed.
Zhu J, He L, Cao Y, Huang R, Li C, Zhang Y, et al.. (2026). STING-GDF15-STAT3 signaling contributes to neuroinflammation after intracerebral hemorrhage.. Experimental neurology. https://doi.org/10.1016/j.expneurol.2026.115804