Table 2.

The circRNA-miRNA-mRNA axis in I/R.

Tissues	Models	Species	Cell dysfunction	Expression	circRNA	miRNA	mRNA	Function	Mechanism	Relationship	Prediction tool	Ref
Myocardial	MI/R in mice and HUVECs under I/R	Human; mouse	Apoptosis; migration	↓	DLGAP4	miR-143	HECTD1	Had no effect on apoptosis in endothelial cells; attenuated the I/R-induced increase in endothelial cell migration	The negative regulation of mimic-miR-143 on HECTD1 protein was abolished by the overexpression of circDLGAP4	NR	Bioinformatics analysis	[61]
	IR	n/a	Apoptosis	↓	DLGAP4	miR-143	Bcl2	A potential regulated therapeutic target of cardiomyocyte apoptosis in myocardial I/R injury	Functions as an endogenous miR-143 sponge	n/a	n/a	[60]
	I/R in mice and H9C2 cells under H2O2 or H/R treatment	Mouse	Apoptosis	↑	NCX1	miR-133a-3p	CDIP1	Knockdown of circNCX1 in murine cardiomyocytes and heart tissues reduced the levels of CDIP1 and attenuated the apoptosis and I/R injury	Acting as an endogenous miR-133a-3p sponge	NR	RNA hybrid	[62]
	IR in mice and mice primary cardiomyocytes under A/R treatment	Mouse	Apoptosis	↑	MFACR	miR-652-3p	MTP18	The knockdown of MFACR attenuated the I/R-induced upregulation of mitochondrial fission, apoptosis, and MI size	Acts as a miR-652-3p sponge	NR	n/a	[63]
	HUVECs under H/R treatment	Human	Proliferation; migration; angiogenesis	↓	circ_100338	miR-200a-3p	FUS	Overexpression of circ_100338 promotes angiogenesis	circ_100338 can indeed regulate angiogenesis by binding to miRNA-200a-3p.	NR	n/a	[65]
	I/R in mice	Mouse	Apoptosis	↑	TLK1	miR-214	RIPK1	Overexpression of RIPK1 led to impaired cardiac function indexes, increased infarct area, and cell apoptosis	Acted as a sponge of miR-214	NR	starBase	[64]
Cerebral	NSCs under OGD/R condition	Mouse	Apoptosis	↑	cZNF292	miR-22	Wnt/b-catenin; PKC/ERK	Silencing cZNF292 alleviated OGD/R-stimulated damage in NSCs	miR-22 expression was negatively regulated by cZNF292	NR	n/a	[116]
	tMCAO/R in mice and mouse primary cortex neurons under OGD/R condition	Human; mouse	Apoptosis; atrophy	↑	TLK1	miR-335-3p	TIPARP	Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficit	Functioned as an endogenous miR-335-3p sponge	NR	RNA hybrid; Arraystar, TargetScan; miRanda	[117]
	MCAO/R in mice	Mouse	Apoptosis	↑	circRNA_008018	miR-99a	PI3K/AKT/GSK3b	Knockdown of circ_008018 attenuated cerebral I/R-induced brain tissue damage and neurological deficits in mice	Inhibits the transcriptional activity of miR-99a	NR	starBase v.2.0; circBase	[118]
	tMCAO/R in mice and mouse primary astrocytes under OGD/R condition	Human; mouse	Autophagy	↑	Hectd1	miR-142	TIPARP	Knockdown of circHectd1 expression significantly decreased infarct areas, attenuated neuronal deficits, and ameliorated astrocyte activation in tMCAO mice	Functions as an endogenous miR-142 sponge	NR	RNA hybrid; TargetScan	[119]
	HT22 cells under OGD/R condition	Mouse	n/a	↑	circRNA_015947	miR-188-3p, miR-329-5p, miR-3057-3p, miR-5098, miR-683	99 target genes	Apoptosis-related pathways; metabolism-related pathways; immune-related pathways	May function as a sponge for its targeted miRNAs	n/a	TargetScan; miRanda	[115]
	HBMECs under OGD/R condition	Human	Proliferation; apoptosis; inflammation	↑	ANRIL	miR-622	p65 and IκBα	Overexpression of circANRIL significantly inhibited the proliferation of OGD/R-induced HBMECs and aggravated OGD/R-induced cell apoptosis	Served as an miR-622 sponge	NR	Bioinformatics analysis	[120]
Hepatic	I/R in mice	Mouse	Inflammation	↑	mmu_circRNA_005186	miR-124-3p	Epha2	mmu_circRNA_005186 silencing attenuated the LPS-induced inflammation	Serving as a miRNA sponge for miR-124-3p	NR	Cytoscape software	[128]
Renal	HK-2 cells under I/R treatment	Human	Apoptosis; inflammation	↓	YAP1	miR-21-5p	PI3K/AKT/mTOR	CircYAP1 overexpression expedited cell growth and weakened secretion of inflammatory factors and ROS generation in I/R-disposed cells	Sponge to miR-21-5p	RC	Circular RNA Interactome	[140]
Intestinal	I/R in mice	Mouse	n/a	↓	circRNA_012412	miR-7649-3p	Sertad1	May play pivotal roles in endogenous protective signaling in iPoC	n/a	n/a	TargetScan; miRanda; miRDB	[149]
				↓	circRNA_012412	miR-3473c	Sertad1
				↓	circRNA_012412	miR-6991-3p	Nudcd1
				↓	circRNA_012412	miR-6991-3p	Jam2

↑: the upward arrow indicates increased expression of circRNAs; ↓: the downward arrow indicates decreased expression of circRNAs; n/a: not applicable; NR: circRNAs negatively regulate miRNAs; PR: circRNAs positively regulate miRNAs; RC: reciprocal correlations between circRNAs and miRNAs; circRNA: circular RNA; miRNAs: microRNAs; IRI: ischemia-reperfusion injury; NSCs: neural stem cells; HUVECs: human umbilical vein endothelial cells; HBMECs: human brain microvascular endothelial cells; tMCAO/R: transient middle cerebral artery occlusion/reperfusion; OGD/R: oxygen-glucose deprivation and reperfusion; H/R: hypoxia-reoxygenation; A/R: anoxia/reoxygenation; NCX1: sodium/calcium exchanger 1; MFACR: mitochondrial fission and apoptosis-related circRNA; ANRIL: antisense noncoding RNA in the INK4A locus; YAP1: yes-associated protein 1; TLK1: serine/threonine-protein kinase tousled-like 1; Bcl2: B-cell lymphoma protein 2; HECTD1: HECT domain E3 ubiquitin protein ligase 1; CDIP1: cell death-inducing protein; MTP18: mitochondrial protein 18 kDa; RIPK1: receptor-interacting serine/threonine-protein kinase 1; Epha2: ephrin type-A receptor 2; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; Sertad1: SERTA domain-containing protein 1; Nudcd1: NudC domain-containing protein 1; Jam2: junctional adhesion molecule B; PKC: protein kinase C; ERK: mitogen-activated protein kinase; TIPARP: TCDD inducible poly(ADP-ribose) polymerase; GSK3B: glycogen synthase kinase 3 beta.