Neurology · Medical Literature
A systematic review on the dual roles of microRNAs in ischemic stroke: mechanisms and effects.
Abstract
MicroRNAs (miRNAs) regulate key pathways in ischemic stroke with both protective and detrimental effects. Understanding these dual roles is important to developing novel therapeutic strategies for cerebral ischemia. This systematic review highlights key miRNAs under investigation, the dysregulation of miRNA expression, and the overall mechanism of miRNA function after ischemic stroke. A total of 20 preclinical in vivo studies from multiple databases (PubMed, Scopus, and Web of Science (WoS)) that modulate miRNA expression post-stroke, published within the last 5 years, were analyzed. To confirm its effectiveness, studies must include miRNA expression level, neurological function test, and infarction volume. Due to the heterogeneity of these studies, as evaluated by the SYRCLE risk of bias tool, a descriptive synthesis was employed to summarize the findings. This review was registered with PROSPERO (CRD42024552558). During the onset of ischemia, there is a sudden upregulation of detrimental miRNAs, accompanied by downregulation of beneficial neuroprotective miRNAs. Beneficial miRNAs inhibited apoptosis, suppressed inflammation, reduced oxidative damage, protected the blood-brain barrier (BBB), promoted angiogenesis, and stimulated neurogenesis. Detrimental miRNAs inhibited critical neuroprotective signaling pathways, suppressed cellular defense mechanisms, promoted Reactive oxygen species (ROS) production, and accelerated ischemic injury. Some miRNAs play dual roles, promoting both apoptosis and neurogenesis. MiRNA modulation demonstrated greater therapeutic potential when used in rationally designed combination therapies, such as two beneficial miRNAs (e.g., miR-210 + miR-126) or a combination of miRNA with other agents (e.g., miR-199a-5p inhibitor + AKT activator IGF-1). Despite the enormous potential of miRNA modulation therapy and numerous preclinical data, translating it from bench to bedside remains a challenge. MiRNAs play dual roles in ischemic stroke, mediating both injury and repair. Their pleiotropic actions position them as promising multi-targeted candidates for stroke therapy, provided translational barriers can be overcome.
Clinical relevance
Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, yet disease-modifying neuroprotective therapies beyond thrombolysis and thrombectomy are severely limited. This systematic review addresses a critical gap by consolidating preclinical evidence on miRNA dysregulation post-stroke, characterizing both injurious and reparative miRNA roles across key pathophysiological cascades including apoptosis, neuroinflammation, oxidative stress, blood-brain barrier integrity, angiogenesis, and neurogenesis. Neurologists and neuroscientists should engage with this literature now as miRNA-based therapeutics represent a plausible next-generation multi-targeted intervention class for cerebral ischemia.
Key findings
1. A systematic analysis of 20 preclinical in vivo studies (sourced from PubMed, Scopus, and Web of Science, published within 5 years of review registration) met stringent inclusion criteria requiring miRNA expression quantification, neurological function assessment, and infarct volume measurement. 2. Ischemia onset triggers rapid upregulation of detrimental miRNAs concurrent with downregulation of neuroprotective miRNAs, establishing a maladaptive post-ischemic miRNA expression landscape that accelerates neuronal injury. 3. Beneficial miRNAs conferred neuroprotection via inhibition of apoptotic cascades, suppression of neuroinflammatory signaling, attenuation of reactive oxygen species (ROS)-mediated oxidative damage, preservation of blood-brain barrier integrity, and promotion of angiogenesis and neurogenesis. 4. Detrimental miRNAs exerted injury by inhibiting critical neuroprotective signaling pathways, suppressing endogenous cellular defense mechanisms, and accelerating ROS production and ischemic cell death. 5. Certain miRNAs exhibited pleiotropic dual roles, simultaneously promoting apoptosis and neurogenesis, underscoring the context-dependent and temporally dynamic nature of miRNA function post-stroke. 6. Combination miRNA modulation strategies demonstrated superior therapeutic potential, with examples including co-administration of two beneficial miRNAs (miR-210 + miR-126) and combined use of a miRNA inhibitor with a pharmacological agent (miR-199a-5p inhibitor + IGF-1 AKT activator), suggesting synergistic multi-pathway engagement; study heterogeneity precluded meta-analysis, and findings are based on descriptive synthesis assessed via the SYRCLE risk of bias tool.
Practice implications
Although no miRNA-based therapies for ischemic stroke are currently approved for clinical use, clinicians and translational researchers should prioritize awareness of the dual — and temporally variable — roles of specific miRNAs (e.g., miR-210, miR-126, miR-199a-5p) when evaluating emerging biomarker and therapeutic trial data, as a single-miRNA targeting approach may be insufficient or context-dependent. Rational combination strategies pairing miRNA modulators with established signaling pathway activators (e.g., IGF-1/AKT axis) represent the most promising translational framework and should be incorporated into future early-phase clinical trial design for neuroprotection in acute ischemic stroke. Significant bench-to-bedside translational barriers — including delivery specificity, off-target pleiotropic effects, and the heterogeneity demonstrated across preclinical models — must be systematically addressed before patient-level application, underscoring the need for standardized in vivo study protocols and validated biomarker endpoints in future research.