International journal of general medicine · 2026
METTL16 Promotes Cerebral Ischemia-Reperfusion Injury via m6A-Dependent Upregulation of TIPARP.
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Xiang Meiling, Han Jiemi, Ye Zai, Chen Bimeng, Wang Hongbo
Аннотация
BACKGROUND: Ischemic stroke leads to severe cerebral ischemia/reperfusion (I/R) injury, resulting in neuronal death and neurological deficits. The N6-methyladenosine (m6A) methyltransferase METTL16 has emerged as a key regulator of RNA metabolism, but its specific role and mechanism in ischemic stroke remain unclear.
METHODS: A transient middle cerebral artery occlusion (MCAO) model was established in adult male C57BL/6J mice. METTL16 was knocked down via intracerebroventricular injection of shRNA-expressing lentivirus at 6 hours post-reperfusion. Cerebral infarct volume (TTC staining), neurological function (mNSS, adhesive removal, corner-turning, and rotarod tests), histopathology (H&E, TUNEL, Nissl, NeuN), and apoptosis-related protein expression were evaluated. Primary cortical neurons and astrocytes were subjected to oxygen-glucose deprivation (OGD). Cell apoptosis, LDH release, inflammatory cytokines (TNF-α, IL-1β), and synaptic protein (Synapsin-1, PSD-95) expression were assessed. The METTL16-TIPARP interaction and m6A modification were analyzed by RIP and m6A-RIP-qPCR. Protein stability was determined using cycloheximide chase assay. Rescue experiments were performed by overexpressing TIPARP in METTL16-depleted cells.
RESULTS: METTL16 knockdown significantly reduced infarct volume, attenuated neuronal apoptosis and inflammation, and improved sensorimotor and coordination functions after MCAO. In vitro, METTL16 depletion protected neurons and astrocytes from OGD-induced apoptosis, cytokine release, and synaptic damage. Mechanistically, METTL16 directly bound to TIPARP mRNA and enhanced its m6A modification, thereby stabilizing TIPARP transcripts and upregulating TIPARP protein expression. Critically, TIPARP overexpression completely abolished the protective effects of METTL16 knockdown against OGD-induced apoptosis and synaptic impairment.
CONCLUSION: METTL16 promotes cerebral I/R injury by stabilizing TIPARP mRNA via m6A methylation, leading to elevated TIPARP expression. The METTL16-m6A-TIPARP axis represents a novel pathogenic mechanism and a potential therapeutic target for ischemic stroke.
METHODS: A transient middle cerebral artery occlusion (MCAO) model was established in adult male C57BL/6J mice. METTL16 was knocked down via intracerebroventricular injection of shRNA-expressing lentivirus at 6 hours post-reperfusion. Cerebral infarct volume (TTC staining), neurological function (mNSS, adhesive removal, corner-turning, and rotarod tests), histopathology (H&E, TUNEL, Nissl, NeuN), and apoptosis-related protein expression were evaluated. Primary cortical neurons and astrocytes were subjected to oxygen-glucose deprivation (OGD). Cell apoptosis, LDH release, inflammatory cytokines (TNF-α, IL-1β), and synaptic protein (Synapsin-1, PSD-95) expression were assessed. The METTL16-TIPARP interaction and m6A modification were analyzed by RIP and m6A-RIP-qPCR. Protein stability was determined using cycloheximide chase assay. Rescue experiments were performed by overexpressing TIPARP in METTL16-depleted cells.
RESULTS: METTL16 knockdown significantly reduced infarct volume, attenuated neuronal apoptosis and inflammation, and improved sensorimotor and coordination functions after MCAO. In vitro, METTL16 depletion protected neurons and astrocytes from OGD-induced apoptosis, cytokine release, and synaptic damage. Mechanistically, METTL16 directly bound to TIPARP mRNA and enhanced its m6A modification, thereby stabilizing TIPARP transcripts and upregulating TIPARP protein expression. Critically, TIPARP overexpression completely abolished the protective effects of METTL16 knockdown against OGD-induced apoptosis and synaptic impairment.
CONCLUSION: METTL16 promotes cerebral I/R injury by stabilizing TIPARP mRNA via m6A methylation, leading to elevated TIPARP expression. The METTL16-m6A-TIPARP axis represents a novel pathogenic mechanism and a potential therapeutic target for ischemic stroke.