CircRNA and ferroptosis in human disease: Insights for new treatments

Abstract

Circular RNA (circRNA), classified as a type of non-coding RNA, has gained significant attention in the field of biology due to its distinctive ring structure and functional properties. Recent research has provided evidence that specific circRNAs have the ability to modulate disease progression through diverse mechanisms, one of which is by regulating cellular ferroptosis. Ferroptosis is a form of regulated cell death that is driven by iron dependency and lipid peroxidation, and extensive investigations have revealed a relationship between ferroptosis and disease development. In addition to evidence that both circRNAs and ferroptosis exert critical roles in disease progression, circRNAs have also been shown to actively mediate the process of ferroptosis. The relationship between circRNAs and ferroptosis therefore influences disease progression and offers novel targets for disease treatment. By directly or indirectly modulating the expression of circRNAs that regulate the expression of ferroptosis-related proteins, it may be possible to impact disease progression by promoting or inhibiting ferroptosis. Current research indicates such approaches may hold significant value in a wide variety of common diseases across physiological systems. This review comprehensively summarizes the findings of recent studies investigating the roles of circRNAs in the regulation of ferroptosis in various diseases.

INTRODUCTION

In 1976, Sanger et al. made the pioneering discovery of circular RNA (circRNA) through electron microscopy analysis of treated plants. Their research revealed the presence of covalently closed-loop RNA molecules, which would later be classified as circRNA.¹ Following the initial discovery of circRNA in plants, subsequent electron microscopy studies observed that RNA molecules present in the cytoplasm of eukaryotic cells exhibit a loop-like structure.² However, for a long time, circRNA was dismissed as a by-product of mis-splicing.³ With the development of high-throughput sequencing and technology, more advanced studies have shown that circRNAs comprise a large class of RNAs that indeed have regulatory functions.⁴ A well-established function of circRNAs is their ability to act as a sponge for microRNAs (miRNAs). In this role, circRNA molecules sequester miRNAs and prevent them from binding to their target messenger RNAs (mRNAs), thereby indirectly regulating gene expression. This competitive binding between circRNAs and miRNAs allows circRNAs to serve as modulators of genetic regulatory networks by influencing the availability and activity of miRNAs.⁵ Following discovery of this function, circRNAs have attracted much greater attention, with studies providing evidence that circRNAs have regulatory roles in a variety of diseases.

As first reported by Dixon et al. (2012), ferroptosis is a relatively newly discovered form of cell death that is distinct from apoptosis, necrosis, and autophagy and is dependent on intracellular iron.⁶ This unique form of cell death was shown to be triggered by erastin⁷ and to possibly be regulated by amino acid and glutathione metabolism, lipid metabolism, and iron metabolism.⁸ The primary underlying mechanisms of ferroptosis involve abnormal accumulation of intracellular iron and lipid peroxides as well as mitochondrial dysfunction. This dysregulation of iron homeostasis, with an abnormal increase in iron accumulation, then contributes to the generation of reactive oxygen species (ROS) and increased lipid peroxidation. Finally, mitochondrial dysfunction can further exacerbate ROS production and lipid peroxide accumulation. The interplay among these mechanisms is crucial to the progression and execution of ferroptotic cell death.⁹ The existing literature indicates that ferroptosis plays a role in a wide range of diseases, providing new targets for their treatment.

The role of circRNAs in regulating ferroptosis has gained significant attention. Several studies have demonstrated that circRNAs can modulate ferroptosis by binding to miRNAs or RNA-binding proteins (RBPs). Through this binding, circRNAs can regulate the expression of various ferroptosis-related genes. One of the key targets of circRNA-mediated regulation in ferroptosis is the enzyme glutathione peroxidase 4 (GPX4). By binding to miRNAs that target GPX4, circRNAs can act as a sponge and prevent miRNA-mediated degradation or inhibition of GPX4 mRNA. By sequestering these miRNAs, circRNAs indirectly promote the expression of GPX4, which is crucial for protecting cells against lipid peroxidation and subsequent ferroptotic cell death. Additionally, circRNAs can interact with miRNAs or RBPs to influence the expression of genes associated with ferroptosis. For instance, circRNA–miRNA or circRNA–RBP interactions can impact the expression of solute carrier family 7 member 11 (SLC7A11), a critical component of the System Xc- antiporter. System Xc- is responsible for cystine uptake and glutathione synthesis, which are important for mitigating the oxidative stress and lipid peroxidation associated with ferroptosis. By modulating the expression level of SLC7A11, circRNAs can indirectly affect cellular susceptibility to ferroptosis. Moreover, circRNAs have been found to indirectly regulate the availability of polyunsaturated fatty acids (PUFAs), which are crucial for lipid peroxidation and ferroptotic cell death. By controlling the expression or activity of enzymes involved in PUFA metabolism, circRNAs can indirectly influence the availability of PUFAs for lipid peroxidation, thereby impacting the occurrence of ferroptosis.

Together these mechanisms reveal that circRNAs can influence complex regulatory networks involved in ferroptosis and provide insights into potential therapeutic targets for modulating ferroptosis-related diseases (Figure 1).

FIGURE 1. The process of regulating ferroptosis. Ferroptosis is regulated by processes such as amino acid and glutathione metabolism, lipid metabolism, and iron metabolism. CircRNAs influence ferroptosis by regulating GPX4 expression, affecting System Xc-, and regulating PUFAs. By Figdraw.

CircRNAs AND DISEASE

CircRNAs are a unique type of ncRNA that has a circular structure, lacks a 5′ cap and a 3′ poly A tail, and is structurally more stable than linear RNA.¹⁰ The known biological functions of circRNAs include: acting as a sponge for miRNAs, transcriptional translation, and interacting with RBPs.¹¹ Because circRNAs have regulatory functions, much research in recent years has explored their use in disease.¹² Peng et al. found that circRNA_010383 can be modified to act as a sponge for miRNA-135a, which down-regulates transient receptor potential cation channel, subfamily C, member 1 (TRPC1), a target of miRNA-135a. Down-regulation of circRNA_010383 promotes the accumulation of extracellular matrix (ECM) proteins, promoting proteinuria, and renal fibrosis in patients with diabetic nephropathy, and can be used as a therapeutic target for diabetic nephropathy.¹³ Additional research showed that circSMAD2 can inhibit the binding of eukaryotic translation initiation factor 4A3 (EIF4A3) to SMAD2 by binding to EIF4A3, thereby affecting the progression of gallbladder cancer.¹⁴ Yuan et al. found that hsa_circ_0072309 promotes autophagy among glioblastoma cells and increases their sensitivity to temozolomide through a P53-dependent mechanism.¹⁵ Furthermore, circRNAs have been used to help diagnose disease based on liquid biopsies of tumors.¹⁶ Existing knowledge of the functions of circRNAs in disease has primarily focused on diagnosis and therapy. However, the regulatory capabilities of circRNAs may also influence disease progression.

ROLE OF FERROPTOSIS IN DISEASE

Ferroptosis has been implicated in the progression of various diseases, including cardiovascular diseases, neurodegenerative diseases, chronic kidney diseases, skin diseases, and others.^17–19 DAZ-associated protein 1 (DAZAP1) is recognized as a potent suppressor of ferroptosis. In hepatocellular carcinoma (HCC) cells, DAZAP1 was shown to bind to SLC7A11 mRNA, positively regulating SLC7A11 expression and inhibiting ferroptosis.²⁰ Fan et al. discovered that early growth response factor 1 (EGR-1) promotes Gpx4 expression by inhibiting miR-15a-5, thereby restraining ferroptosis in cardiomyocytes and reducing myocardial injury.²¹ In Alzheimer's disease patients, amyloid beta 1–40 (Aβ1–40) triggers ferroptosis in phagocytes through the CD36/PINK/Parkin pathway, leading to disruption of the blood–brain barrier.²² Zhao et al. demonstrated that XJB-5-131 acts as a ferroptosis inhibitor, limiting both ferroptosis and lipid peroxidation in renal tubular epithelial cells after renal ischemia–reperfusion injury.²³ Together this research collectively indicates that the cell death mechanism of ferroptosis holds significant potential for therapeutic approaches to various diseases.

CircRNAs REGULATE FERROPTOSIS IN DISEASE

Several studies have investigated the individual roles of circRNAs and ferroptosis in various diseases, prompting the question of a potential link between circRNAs and ferroptosis. CircRNAs, as ncRNAs with regulatory functions, are known to be able to regulate ferroptosis in cells, and thus multiple studies have explored various mechanisms through which circRNAs regulate ferroptosis, with their results offering novel insights for new strategies for disease diagnosis and treatment. To gather relevant information, we searched the PubMed database for studies published between 2020 and 2023 using the keywords “circRNAs” and “ferroptosis”. All selected studies provided thorough experimental validation and were categorized according to different physiological systems (Figure 2). Overall, these investigations identified diverse mechanisms through which circRNAs regulate ferroptosis, presenting insights for the development of more effective methods for disease diagnosis and treatment. A comprehensive summary of this research is presented in Table 1.

FIGURE 2. CircRNAs regulate ferroptosis in disease. In different systemic diseases, circRNAs affect disease progression by promoting or inhibiting ferroptosis, and may play a role in treating the disease. By Figdraw.

TABLE 1 The role of circRNAs regulation of ferroptosis in disease.

CircRNA	Disease	Relationship	Pathway	Target	Function	Ref
circDTL	NSCLC	Promotion	circDTL/miR1287-5p/GPX4	GPX4	Improve drug sensitivity	24
circP4HB	LUAD	Inhibition	circP4HB/miR-1184/SLC7A11	SLC7A11	Diagnosis and treatment	25
circRNA_101093	LUAD	Inhibition	Cir93/FABP3/AA	AA	Treatment	26
circSCN8A	NSCLC	Promotion	circSCN8A/miR-1290/ACSL4	ACSL4	Treatment	27
circSAV1	COPD	Promotion	circSAV1/YTHDF1/IREB2	IREB2	Treatment	28
circ_0007142	CRC	Inhibition	circ_0007142/miR-874-3p/GDPD5	GDPD5	Treatment	29
circBCAR3	ESCA	Inhibition	CircBCAR3/miR-27a-3p/TNPO1	TNPO1	Treatment	30
circIL4R	HCC	Inhibition	circIL4R/miR-541-3p/GPX4	GPX4	Treatment	31
hsa_circ_0008367	HCC	Inhibition	hsa_circ_0008367/ALKBH5	ALKBH5	Treatment	32
circ0097009	HCC	Inhibition	circ0097009/miR-1261/SLC7A11	SLC7A11	Treatment	33
circ_0000190	GC	Promotion	circ_0000190/miR-382-5p/ZNRF3	ZNRF3	Diagnosis and treatment	34
circRNA1615	MI	Inhibition	circRNA1615/miRNA1523p/LRP6	LRP6	Diagnosis and treatment	35
circSnx12	HF	Inhibition	circSnx12/miR-224-5p/FTH1	FTH1	Treatment	36
circST6GALNAC6	Bladder cancer	Promotion	circST6GALNAC6/HSPB1/P38	HSPB1	Biomarker	37
circGFRA1	Breast cancer	Inhibition	circGFRA1/miR-1228/AIFM2	AIFM2	Treatment	38
hsa_circRNA_000479	CC	Inhibition	hsa_circRNA_000479/miR-375/409-3P/515-5p-SLC7A11	SLC7A11	Biomarker	39
circLMO1	CC	Promotion	circLMO1/miR-4291/ACSL4	ACSL4	Treatment	40
circRHOT1	Breast cancer	Inhibition	circRHOT1/miR-106a-5p/STAT3	STAT3	Treatment	41
circRHBG	PCOS	Inhibition	circRHBG/miR-515-5p/SLC7A11	SLC7A11	Diagnosis and treatment	42
circ-BGN	Breast cancer	Inhibition	circ-BGN /OTUB1/SLC7A11	SLC7A11	Drug resistance	43
circRAPGEF5	EC	Inhibition	circRAPGEF5/RBFOX2	RBFOX2	Treatment	44
circ_0067934	TC	Inhibition	circ_0067934/miR-545-3p/SLC7A11	SLC7A11	Treatment	45
circKIF4A	TC	Inhibition	circKIF4A/miR-1231/GPX4	GPX4	Treatment	46
mmu_circRNA_0000309	DN	Inhibition	mmu_circRNA_0000309/miR-188-3p/GPX4	GPX4	Drug resistance	47
circ-ITCH	DFU	Inhibition	circ-ITCH /TAF15/Nrf2	Nrf2	Treatment	48
cir-Carm1	ACI	Inhibition	cir-Carm1/miR-3098-3p/ACSL4	ACSL4	Treatment	49
mmu_circ_0000130	TBI	Promotion	mmu_circ_0000130/miR-351-5p/5-LOX	5-LOX	Treatment	50
circCDK14	Glioma	Inhibition	circCDK14/miR-3938/PDGFRA	PDGFRA	Treatment	51
circ_0000745	ALL	Inhibition	circ_0000745/miR-494-3p/NET1	NET1	Biomarker	52
circZBTB46	AML	Inhibition	circZBTB46/miR-671-5p/SCD	SCD	Treatment	53
circ-Ash1l	Skin injury	Inhibition	circ-Ash1l/miR-700-5p/GPX4	GPX4	Treatment	54

Disease of the respiratory system

One of the most studied respiratory diseases is lung cancer, currently one of the most prevalent cancers worldwide.⁵⁵ Wang et al. found that circDTL exerts pro-cancer effects through the circDTL/miR1287-5p/Gpx4 axis and showed that inhibition of circDTL can inhibit both ferroptosis and apoptosis, thereby increasing the sensitivity of non-small cell lung cancer (NSCLC) cells to chemotherapeutic agents.²⁴ CircP4HB was found to suppress ferroptosis in lung adenocarcinoma (LUAD) as well as to inhibit ferroptosis by regulating the miR-1184/SLC7A11 axis, and this mechanism may provide targets for strategies for the early diagnosis and treatment of LUAD.²⁵ Exosomal circRNA_101093 (cir93) maintains intracellular cir93 elevation in LUAD to regulate arachidonic acid (AA), thereby reducing LUAD cell sensitivity to ferroptosis. Therefore, Zhang et al. proposed that blocking exosomal circRNA_101093 may be beneficial in the treatment of LUAD.²⁶ CircSCN8A was shown to induce ferroptosis among NSCLC cells by regulating the miR-1290/ACSL4 axis and thereby to inhibit NSCLC cell proliferation and metastasis.²⁷ Xia et al. found that N6-methyladenosine-modified circSAV1 can trigger ferroptosis in chronic obstructive pulmonary disease (COPD) by promoting iron-responsive element-binding protein 2 (IREB2) translation through recruitment of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), and thus circSAV1-dependent ferroptosis represents a therapeutic target for COPD.²⁸ Together, the results of the aforementioned studies demonstrate that specific circRNAs possess the ability to influence ferroptosis in lung cancer cells. Accordingly, if circRNA expression can be manipulated to increase ferroptosis among tumor cells, such approaches could potentially contribute to the treatment of lung cancer. Additionally, respiratory system conditions such as pneumonia, bronchiectasis, and asthma are prevalent, and future research is expected to delve into the roles of circRNAs and ferroptosis in these pathologies.

Diseases of the digestive system

The numerous diseases affecting the digestive system include various types of tumors, and considerable research in this area has shown that circRNA regulation of ferroptosis provides new targets for the treatment of tumors in the digestive system. Wang et al. found that the circ_0007142/miR-874-3p/GDPD5 axis regulates tumorigenesis and ferroptosis in colorectal cancer (CRC) cells, and that inhibition of circ_0007142 gene expression promotes apoptosis and ferroptosis among these cells, resulting in diminished CRC cell proliferation.²⁹ Xi et al. showed that circBCAR3 can interact with miR-27a-3p through a competitive endogenous RNA mechanism, and such interaction leads to increased transportin-1 (TNPO1) expression and promotes ferroptosis among esophageal cancer cells.³⁰ CircIL4R was identified as a potential target for the treatment of HCC in a study showing that it promotes hepatocellular carcinogenesis by regulating the miR-541-3p/Gpx4 axis and also by inhibiting ferroptosis.³¹ Another study found that hsa_circ_0008367 binds to ALKB homolog 5 (ALKBH5) to inhibit ferroptosis, which significantly reduces the sensitivity of HCC cells to sorafenib (SF) or erastin.³² Circ0097009 also was shown to inhibit ferroptosis in HCC cells by acting as a sponge for miR-1261 to regulate the expression of SLC7A11, a key regulator of ferroptosis in HCC, thereby providing a new target for HCC treatment.³³ Circ_0000190 was found to act as a miR-382-5p sponge to regulate Zing and Ring Finger 3 (ZNRF3) expression and promote ferroptosis in gastric cancer (GC) cells, thereby inhibiting GC cell proliferation and migration.³⁴ Tumors of the digestive system remain a serious threat to human health, and current treatment options of surgery and chemotherapy offer limited effectiveness. The research summarized above indicates that circRNAs can improve the sensitivity of these tumors to chemotherapy drugs by promoting ferroptosis. Therefore, linking circRNAs and ferroptosis may be useful for improved methods to diagnose these tumors and predict their progression and drug resistance.

Diseases of the cardiovascular system

Recent studies have revealed a close relationship between ferroptosis and cardiovascular disease, while circRNAs are also known to play important roles in cardiovascular disease. Thus, the two may be related in cardiovascular diseases. Consistently, research indicates that circRNAs can regulate ferroptosis and provide a new therapeutic target for cardiovascular disease.⁵⁶ Cardiovascular diseases known to be associated with ferroptosis include cardiac ischemia/reperfusion injury, heart failure (HF), cardiac hypertrophy, vascular calcification, endothelial dysfunction, aortic aneurysm, among other diseases.⁵⁷ CircRNA1615 was found to regulate cardiomyocyte autophagy through the miRNA1523p/LRP6 molecular axis and to consequently inhibit ferroptosis in cardiomyocytes, findings that could be useful in new methods for diagnosing and treating myocardial infarction (MI).³⁵ Zheng et al. constructed a circRNA–miRNA–mRNA network to study the involvement of circSnx12 and miR-224-5p targeting the FTH1 gene, which encodes a ferroptosis inhibitor, in the ferroptosis of cardiomyocytes during HF and provided evidence that circSnx12 may be a potential therapeutic target for the treatment of HF.³⁶ Because circRNAs could serve as non-invasive biomarkers, knowledge of their roles in cardiovascular diseases can help us develop new methods to diagnose and treat cardiovascular diseases that target the activity of circRNAs in relation to ferroptosis.

Diseases of the urinary system

Relatively few studies have investigated the roles of circRNAs in ferroptosis in the context of urinary diseases. One study found that CircST6GALNAC6 inhibits small heat shock protein 1 (HSPB1) by occupying the phosphorylation site (Ser-15) of HSPB1 and activating the P38 MAPK signaling pathway, thereby promoting ferroptosis in bladder cancer cells.³⁷ Their finding suggests that this specific circRNA can be used as a biomarker of ferroptosis sensitivity in bladder cancer but also that it regulates ferroptosis in a different way from most circRNAs previously examined. This research provides insight that circRNAs may promote ferroptosis through a variety of different mechanisms. More research is needed to determine whether this action of a circRNA in bladder cancer is applicable in other urological diseases.

Diseases of the reproductive system

Among reproductive system diseases, tumors remain the most extensively studied pathologies because they pose such a severe threat to human health. Accordingly, novel ideas for the early diagnosis and treatment of these tumors are widely sought. A study by Bazhabayi et al.³⁸ demonstrated that CircGFRA1 mitigates the inhibition of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) by binding to miR-1228. Conversely, inhibiting the expression of CircGFRA1 was shown to enhance ferroptosis in breast cancer cases with positive expression of the human epidermal growth factor receptor 2 (HER2) gene. Another study reported by Wu et al.³⁹ identified Hsa_circRNA_000479 as a potential therapeutic target for cervical cancer (CC), because it promotes the expression of SLC7A11 and thereby inhibits ferroptosis in CC cells. Another circRNA, CircLMO1, was found to induce ferroptosis in CC cells by upregulating ACSL4 expression, highlighting its potential as a significant biomarker for clinical treatment of CC.⁴⁰ Furthermore, Zhang et al.⁴¹ discovered that CircRHOT1 binds to microRNA106a-5p (miR-106a-5p) and facilitates breast cancer progression by downregulating miR-106a-5p to inhibit ferroptosis in breast cancer cells. CircRHBG was proposed to inhibit ferroptosis in granulosa cells associated with polycystic ovary syndrome (PCOS) through a CircRHBG/miR-515-5p/SLC7A11 axis, and thus to represent a potential diagnostic and therapeutic biomarker for PCOS.⁴² Circ-BGN, on the other hand, was shown to inhibit ferroptosis in HER2-positive breast cancer cells by binding to OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) and SLC7A11, and this regulation of ferroptosis was found to mediate trastuzumab resistance in HER2-positive breast cancer.⁴³ In endometrial cancer (EC), CircRAPGEF5 was shown to promote transferrin formation via exon 4 and to facilitate resistance to ferroptosis in EC cells through interaction with RNA-binding Fox-1 homolog 2 (RBFOX2).⁴⁴ These studies support continued comprehensive and in-depth exploration of circRNAs that influence ferroptosis as promising targets for therapeutic approaches for tumors of the reproductive system.

Diseases of the endocrine system

Most endocrine diseases are chronic diseases that are common in the population and affect quality of life, making the discovery of new therapeutic targets of great significance.⁵⁸ Circ_0067934 was found to inhibit ferroptosis in thyroid cancer cells via a miR-545-3p/SLC7A11 axis, thus providing a new therapeutic target for thyroid cancer.⁴⁵ Chen et al. found that CircKIF4A enhances GPX4 expression by binding with miR-1231 and thereby affects the proliferation of thyroid papillary cancer cells and inhibits ferroptosis.⁴⁶ It was shown that mmu_circRNA_0000309 can act as a miR-188-3p sponge to upregulate GPX4 expression and inactivate ferroptosis-dependent mitochondrial function and podocyte apoptosis. Also, inhibition of mmu_circRNA_0000309 affected resistance to germacrone in mice with diabetic nephropathy.⁴⁷ Recruitment of TAF15 protein by circ-ITCH in diabetic foot ulcer to activate the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway and inhibit ferroptosis was shown to promote angiogenic capacity and accelerate wound healing.⁴⁸ These studies provide new ideas for the clinical treatment of endocrine system disorders.

Diseases of the nervous system

The control of ferroptosis via targeting circRNAs that regulate it has been proposed as a therapeutic approach for nervous system diseases.⁵⁹ Mao et al. found that cir-Carm1 deficiency protects against acute cerebral ridge acute cerebral infarction (ACI) by regulating the miR-3098-3p/ACSL4 axis to inhibit ferroptosis and, therefore, may be used as a therapeutic strategy for ACI.⁴⁹ Wu et al. found that mmu_circ_0000130 can positively regulate the expression of 5-lipoxygenase (5-LOX) associated with ferroptosis by acting as a miR-351-5p sponge, while melatonin can reduce lipid peroxidation through the circPtpn14/miR-351-5p/5-LOX axis, thus exerting an anti-ferroptosis effect in traumatic brain injury.⁵⁰ In the context of neurological tumors, circCDK14 was found to reduce the sensitivity of glioma cells to ferroptosis by regulating platelet-derived growth factor receptor alpha (PDGFRA) expression, thereby promoting tumor progression.⁵¹ Previous studies have shown that ferroptosis regulation is a valuable approach in the study and potentially treatment of Alzheimer's disease. Considering there have been many studies of the roles of ncRNAs in Alzheimer's disease, research into the combined effects of ncRNAs and circRNAs may be beneficial.

Diseases of the hematological system

The treatment of blood system diseases is difficult, and the existing research has focused mainly on acute leukemia.⁶⁰ Circ_0000745 was found to act as a sponge for miR-494-3p to positively regulate neuroepithelial cell transforming 1 (NET1) expression, thereby promoting cell cycle progression and glycolysis and inhibiting ferroptosis in acute lymphoblastic leukemia (ALL) cells.⁵² Another study showed that CircZBTB46 may up-regulate the expression of stearoyl-CoA desaturase 1 (SCD) by acting as a miRNA sponge, and the loss of CircZBTB46 enhances ferroptosis in RSL3-induced acute myeloid leukemia (AML) cells, suggesting its potential as a therapeutic target for AML.⁵³ These early studies suggest mediation of cell ferroptosis may represent a novel treatment approach for acute leukemias.

Diseases of other systems

CircRNA regulation of ferroptosis has been studied in the context of other common diseases not related to the systems listed above. Zha et al. observed that adipose-derived stem cell-derived exosomes preconditioned with exposure to hypoxia can attenuate ultraviolet (UV) radiation-induced skin injury through circ-Ash1l delivery, iron antagonism, and inhibition of GPX4-mediated ferroptosis of cells.⁵⁴ Regulation of ferroptosis by circRNAs as a means to attenuate UV-induced skin damage is an interesting concept, and the influence of circRNA regulation of ferroptosis is worth exploring in many other diseases in the future.

CONCLUSION

In summary, the regulation of ferroptosis by circRNAs holds promise as a novel therapeutic approach for various diseases, and greater focus has been given to its study in tumors versus other diseases to date. The current research is basically related to treatment and how alteration of circRNA expression to promote or inhibit cell ferroptosis can play a therapeutic purpose, which is a new idea for treating diseases. Accordingly, studies have shown that adjusting CircDTL expression can improve the sensitivity of NSCLC cells to chemotherapy drugs, adjusting hsa_circ_0008367 expression can improve the sensitivity of HCC cells to SF or erastin, and adjusting circ-BGN expression can reduce the resistance of HER2-positive breast cancer to trastuzumab. Additionally, regulation of mmu_circRNA_0000309 expression can affect the resistance of mice with diabetic neuropathy to germacrone. In all of these examples, changes in expression of a circRNA affect the sensitivity of the diseased cells to a drug by regulating ferroptosis, leading to reduced drug resistance and potential treatment of the disease. circSAV1, circ-ITCH, CIRR-CARM1, mmu_circ_0000130, circCDK14, and circ-Ash1l all achieve therapeutic effects by inhibiting cell ferroptosis. Circ-ITCH also promotes angiogenesis and accelerates wound healing. The remaining CircP4HB, circRNA_101093, CircSCN8A, etc. may have therapeutic significance in tumors and can be used to treat tumors by promoting ferroptosis of tumor cells and inhibiting cell proliferation. Successful regulation of circRNA expression in vivo is the key to circRNA therapy. In short, RNA interference⁶¹ and CRISPR/Cas Systems⁶² are used to knock down circRNAs, while overexpression of circRNAs is mainly achieved through synthetic circRNAs⁶³ and viral vectors.⁶⁴ Exosome and nanoparticle delivery are being explored as circRNA delivery systems.^65,66 Despite the high stability of circRNAs, there are still some risks. Interference and overexpression of circRNAs may result in incorrect splicing, reducing interference and overexpression efficiency and may even present unpredictable safety risks. Moreover, some circRNAs may affect more than one kind of cell or tissue. Off-target effects may lead to disease exacerbation or even the emergence of new diseases.⁶⁷ Further research on how to improve the safety of circRNA therapy and eliminate off-target effects is needed in the future. Perhaps improving the delivery systems can reduce off-target effects.

Based on the studies summarized in Table 1, it has been observed that circRNAs primarily regulate ferroptosis by functioning as miRNA sponges, thereby impacting downstream expression of ferroptosis-related proteins. Alternatively, circRNAs can bind to RBPs to regulate ferroptosis-related protein activity, or even directly to ferroptosis-related proteins. Ferroptosis is a mode of cell death distinct from apoptosis, and its morphological features include condensed or swollen mitochondria, loss of mitochondrial cristae, and rupture of the outer membrane, accompanied by loss of mitochondrial membrane potential.^68,69 Overall, research to date indicates that the main inhibitors of ferroptosis are GPX4, SLC7A11, and iron regulatory protein 2 (IRP2), and the main promoters are tumor protein 53 (P53) and acyl-CoA synthetase long chain family member 4 (ACSL4).^70–74 CircRNAs, as non-coding RNAs (ncRNAs) with a stable ring-like structure, have also been considered as novel biomarkers of disease that can be used in diagnosis, treatment, and prognosis.^75,76,77 Because circRNAs are stable in peripheral blood, urine, and saliva due to their special structure, they can be detected in non-invasive or minimally invasive ways.⁷⁸ When experimental evidence demonstrates that some specific circRNAs can influence disease progression via the regulation of ferroptosis, further research is warranted to determine whether the disease can be diagnosed based on detection of that circRNAs in bodily fluids and whether regulation of cellular ferroptosis by alteration of the circRNAs expression can effectively treat the disease. According to the studies described above relating to tumors, ferroptosis can influence the sensitivity of tumor cells to chemotherapeutic drugs and related approaches could contribute to clinical dosing.

As mentioned previously, there are many studies on circRNA regulation of ferroptosis, the majority of which are on tumors. Cancer, as a disease with a high mortality rate, is a serious risk to human health, and if research in this area can help people diagnose and treat it, then more people will benefit from it. Studies on ferroptosis have also shown that it is closely associated with neurodegenerative disease and cardiovascular disease. CircRNAs are known to have many functions, but research on their regulation of ferroptosis is mostly concerned with their function as miRNA sponges and their interactions with RBP, so it is hoped that there will be new breakthroughs in other pathways. In addition, it might be more useful for clinical purposes if more research is done on drug therapy.

Future research is expected to provide further valuable insights into the effects of circRNAs on ferroptosis and the regulatory role of this relationship in human diseases. In addition to their established roles as miRNA sponges, circRNAs are known to have diverse functions, prompting the need for investigations into other potential functions in the context of disease. Animal experiments should be prioritized to verify the therapeutic impact of circRNA regulation of ferroptosis in various diseases. In conclusion, circRNAs hold potential as biomarkers for disease diagnosis, therapy, and prognosis, and their modulation of ferroptosis through various mechanisms is likely to aid in disease treatment.

AUTHOR CONTRIBUTIONS

Ruoyu Liu wrote the manuscript. Yongtong Cao and Yun Zhou did review and revision of the manuscript. All the authors read and approved the final manuscript.

ACKNOWLEDGMENTS

Not applicable.

FUNDING INFORMATION

This work was financially supported by the National Natural Science Foundation of China (82272407, 82072337); Key Clinical Specialty Project of Beijing (2020).

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.