Experimental cell research · 2026
Circ_0000376 protects against post cardiac arrest brain injury by sponging mmu-let-7b-5p to preserve CCND1 and metabolic homeostasis.
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Lin Long, Zhao Yingtong, Liu Xiong, Huang Xiaodong, Huang Xianwei, Pan Mandong, Lin Jiyan
Аннотация
BACKGROUND: Post cardiac arrest brain injury (PCABI) results from global ischemia-reperfusion. Circular RNAs (circRNAs) are stable regulators of post transcriptional networks that may modulate neuronal survival and metabolism after ischemic injury. We investigated the role and mechanism of mmu_circ_0000376 (circ_0000376) in PCABI.
METHODS: Through integrated bioinformatics analysis of circular RNA/microRNA/messenger RNA datasets via the GEO platform, a regulatory network involving circ_0000376/mmu-let-7b-5p/CCND1 was identified. We validated its circular structure, stability, and cytoplasmic localization in HT22 neuronal cells. Through in vitro and in vivo experiments modulating circ_0000376 expression, we investigated cellular functions by assessing cell viability, apoptosis (Annexin V/PI staining, TUNEL, caspase/Bcl-2 family proteins), and mitochondrial/energy parameters (ATP, glucose consumption, lactate, G6PD activity).
RESULTS: Circ_0000376 is a stable, cytoplasmic circRNA. Overexpression of Circ_0000376 reduced ischemia-reperfusion injury induced ROS, preserved ATP and glycolytic flux, increased G6PD activity, decreased apoptosis, and restored CCND1 and Bcl 2 while lowering Bax and cleaved caspases. Bioinformatic and reporter assays showed circ_0000376 sponges mmu-let-7b-5p, relieving repression of CCND1. mmu-let-7b-5p overexpression or CCND1 knockdown reversed circ_0000376 mediated protection. AAV mediated circ_0000376 overexpression in mice decreased hippocampal apoptosis and restored CCND1 in vivo.
CONCLUSIONS: Circ_0000376/mmu-let-7b-5p/CCND1 axis mitigates neuronal apoptosis and metabolic dysfunction after ischemic injury. Targeting this ceRNA network may offer a novel neuroprotective strategy for PCABI.
METHODS: Through integrated bioinformatics analysis of circular RNA/microRNA/messenger RNA datasets via the GEO platform, a regulatory network involving circ_0000376/mmu-let-7b-5p/CCND1 was identified. We validated its circular structure, stability, and cytoplasmic localization in HT22 neuronal cells. Through in vitro and in vivo experiments modulating circ_0000376 expression, we investigated cellular functions by assessing cell viability, apoptosis (Annexin V/PI staining, TUNEL, caspase/Bcl-2 family proteins), and mitochondrial/energy parameters (ATP, glucose consumption, lactate, G6PD activity).
RESULTS: Circ_0000376 is a stable, cytoplasmic circRNA. Overexpression of Circ_0000376 reduced ischemia-reperfusion injury induced ROS, preserved ATP and glycolytic flux, increased G6PD activity, decreased apoptosis, and restored CCND1 and Bcl 2 while lowering Bax and cleaved caspases. Bioinformatic and reporter assays showed circ_0000376 sponges mmu-let-7b-5p, relieving repression of CCND1. mmu-let-7b-5p overexpression or CCND1 knockdown reversed circ_0000376 mediated protection. AAV mediated circ_0000376 overexpression in mice decreased hippocampal apoptosis and restored CCND1 in vivo.
CONCLUSIONS: Circ_0000376/mmu-let-7b-5p/CCND1 axis mitigates neuronal apoptosis and metabolic dysfunction after ischemic injury. Targeting this ceRNA network may offer a novel neuroprotective strategy for PCABI.