Restoration of miR-642b-3p alleviates post-ICH cerebral edema and neurological deficits via targeted inhibition of SERPINE1-mediated inflammation, involving suppression of NLRP3 inflammasome and promotion of M2 polarization.
Key Findings
Results
miR-642b-3p was decreased while SERPINE1 was increased in serum of ICH patients compared to healthy controls.
66 ICH patients and 70 matched healthy controls were enrolled with strict inclusion/exclusion criteria.
Expression differences were observed in patient serum samples.
Hematoma volume and GCS score were identified as independent predictors of miR-642b-3p and SERPINE1 expression via multivariable linear regression.
The same directional expression changes were observed in rat brain tissue from collagenase-induced ICH models.
Results
miR-642b-3p directly binds to the 3'UTR of SERPINE1, confirming a direct regulatory relationship.
Direct binding was verified using a dual-luciferase reporter assay.
miR-642b-3p overexpression suppressed SERPINE1 expression in vivo and in vitro.
SERPINE1 overexpression rescue experiments confirmed that the protective effects of miR-642b-3p were mediated through SERPINE1.
LPS-stimulated BV-2 microglia were used as the in vitro model system.
Results
Intracerebroventricular injection of miR-642b-3p agomir improved neurological function and reduced brain edema in rat ICH models.
Rats received intracerebroventricular injection of 5 nmol/rat miR-642b-3p agomir.
Collagenase-induced rat ICH models were established with pre-calculated sample size, random grouping, and blinded tests.
Neurological function was assessed via modified Neurological Severity Score (mNSS) and modified Lateral Pushing Test (mLPT).
Brain edema was measured alongside neurological outcomes, with miR-642b-3p overexpression shown to relieve edema.
Results
miR-642b-3p overexpression lowered proinflammatory cytokine levels in vivo following ICH.
Inflammatory cytokines were detected via ELISA.
miR-642b-3p overexpression reduced proinflammatory cytokines in the rat ICH model.
In LPS-treated BV-2 cells, miR-mimic reversed abnormal SERPINE1 elevation and associated inflammation.
SERPINE1 overexpression abolished the anti-inflammatory protective effects of miR-642b-3p, confirming the mechanistic link.
Results
miR-642b-3p inhibited NLRP3 inflammasome activation by targeting SERPINE1.
NLRP3 inflammasome components were assessed by qPCR.
The effect on NLRP3 inflammasome was mediated through targeted inhibition of SERPINE1.
This mechanism was assessed in the context of post-ICH neuroinflammation.
Results
miR-642b-3p promoted microglial M2 polarization by targeting SERPINE1.
Microglial polarization markers were assessed by qPCR.
miR-642b-3p shifted microglia toward the anti-inflammatory M2 phenotype.
This polarization effect was mediated through the miR-642b-3p/SERPINE1 regulatory axis.
BV-2 microglia were used as the cellular model for assessing polarization states.
What This Means
This research suggests that a small RNA molecule called miR-642b-3p plays a protective role after a type of stroke known as intracerebral hemorrhage (ICH), where bleeding occurs directly into the brain. The study found that people who had experienced ICH had lower levels of miR-642b-3p and higher levels of a protein called SERPINE1 in their blood compared to healthy people, and the severity of the bleed (measured by hematoma volume and consciousness scores) predicted how abnormal these levels were. When researchers artificially restored miR-642b-3p levels in rats with ICH, the animals had less brain swelling, better neurological function, and lower levels of harmful inflammatory proteins.
The study also identified the biological mechanism behind these effects. miR-642b-3p directly binds to and suppresses SERPINE1, and this suppression in turn reduces activation of the NLRP3 inflammasome — a cellular alarm system that drives dangerous inflammation — and shifts immune cells in the brain called microglia from an inflammatory state to a more protective, anti-inflammatory state called M2 polarization. When researchers artificially raised SERPINE1 levels back up in cell experiments, the protective effects of miR-642b-3p disappeared, confirming that SERPINE1 is the key target.
This research suggests that the miR-642b-3p/SERPINE1 pathway could be a promising target for developing new treatments for brain injury after hemorrhagic stroke. The findings provide a molecular explanation for how this small RNA protects the brain and may help guide future therapeutic strategies aimed at reducing the brain swelling and neurological damage that follow this serious type of stroke.
Rao Z, Li J. (2026). Protective effect of miR-642b-3p against brain injury after intracerebral hemorrhage by targeting SERPINE1.. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. https://doi.org/10.1016/j.jstrokecerebrovasdis.2026.108739