The emerging roles of circHECTD1 in human diseases and the specific underlying regulatory mechanisms

circRNAs, as competing endogenous RNAs (ceRNAs) or miRNA molecular sponges, regulate the expression of miRNA-targeted genes

The miRNA sponge role of circRNAs is a popular area of research. miRNAs can regulate mRNA stability and translation by complementary binding to the 3′-untranslated regions (UTRs) of mRNAs, resulting in reduced target protein synthesis without affecting mRNA expression levels (Pillai, 2005). However, circRNAs have abundant miRNA-binding sites and can act as ceRNAs to competitively repress miRNAs or as molecular sponges to adsorb miRNAs and thus upregulate the protein expression of their target genes (Panda, 2018). circHIPK3 inhibits its complementary binding to IGF1 mRNA by sponging miR-379 and upregulates IFG1 protein expression thereby promoting the development of non-small cell lung cancer (NSCLC) (Tian et al., 2017). Wang et al. (2019) reported that circHIAT1 acts as a miR-3171 sponge to upregulate PTEN in hepatocellular carcinoma (HCC), thereby promoting HCC development. The role of miRNA sponges of circRNAs suggests that circRNAs can regulate the level of gene expression, which is not only related to the development of various diseases, but also facilitates further research on the molecular regulation of diseases and improves the understanding of the molecular regulatory network of diseases (Fig. 2A).

circRNAs promote RNA polymerase II-mediated gene transcription

It has been shown that EIciRNAs are abundantly enriched in the nucleus, and EIciRNAs promote gene expression by forming the eiciRNA-U1 SnRNP complex through RNA–RNA interactions with U1 SnRNA, which then interacts with the RNA polymerase II transcriptional complex on the parental gene promoter (Li et al., 2015). Zhang et al. (2013) found that ciRNA-ANKRD52 could interact with RNA polymerase II to promote transcription, and knockdown of ciRNA-ANKRD52 would not affect the binding of ciRNA to RNA polymerase II or the expression of ANKRD52 but would reduce the rate of ANKRD52 gene transcription (Fig. 2B).

circRNAs regulate protein function by interacting directly with proteins

Many circRNAs have been found to regulate protein functions through interactions with RNA-binding proteins (RBPs). For example, circ-Amotl1 can interact with phosphoinositide dependent kinase (PDK1) and serine/threonine kinase (AKT1), leading to the promotion of pAKT expression and nuclear ectopia in primary cardiomyocytes and protection against myocardial injury caused by anthracycline doxorubicin (Zeng et al., 2017). CircARSP91 can bind to UL16-binding protein 1 (ULBP1), promoting the cytotoxicity of natural killer cells against HCC. CircARSP91 can also bind to adenosine deaminase that acts on RNA (ADAR1), inhibiting HCC growth (Ma et al., 2019; Shi et al., 2017). CircRNA-SORE impedes the ubiquitination and degradation of Y-box binding protein 1 (YBX1) by binding to the YBX1 protein, thereby enhancing HCC resistance to sorafenib (Xu et al., 2020). Interestingly, bioinformatics analysis revealed that circRNAs bind less densely to RBPs than to linear RNAs via nucleotide sequence-based binding (Du et al., 2017). However, existing studies suggest that the binding of RNA to RBPs is also influenced by the tertiary structure of the RNA molecule. It can be speculated that circRNAs have a more complex binding mechanism to RBPs due to their unique tertiary structure. The mechanism of interaction between circRNAs and RBPs still requires further exploration (Abe et al., 2015; Loughlin et al., 2019) (Fig. 2C).

circRNAs as translation templates that encode proteins

Initially, circRNAs were not thought to be able to be translated into proteins. Later, as technological advancements revealed that most circRNAs originate from protein-coding exons in the cytoplasm, circRNAs were thought to have the potential to encode proteins. Currently, some circRNAs have been found to encode proteins both in vivo and in vitro (Chen & Sarnow, 1995). Because circRNAs do not possess a free 5′terminal cap structure, they cannot be translated through the conventional pathway but need to be methylated, specifically via N6-methyladenosine (m6A), at an internal ribosome entry site (IRES) or within the 5′ untranslated region (5′ UTR). Methylation of adenosine residues by m6A on the 5′ cap-end initiates protein translation through a 5′ non-cap dependent pathway (Diallo et al., 2019; López-Lastra, Rivas & Barría, 2005). CircPINT exon 2 is formed by reverse splicing of exon 2 of LINC-PINT, and Zhang et al. (2018a) reported that circPINT exon 2 has a natural IRES structure that encodes the PIN87aa peptide, which contains 87 amino acids and has comprehensive tumour-suppressive effects. circ-AKT3 encodes AKT3-174aa, a protein containing 174 amino acids that inhibits the malignant biological behaviour of gliomas and enhances their resistance to radiotherapy when overexpressed (Xia et al., 2019). Out of the 32,914 human ecircRNAs selected, 7,170 had IRES elements, indicating their protein-coding potential. Additionally, evidence exists for 37 circRNAs encoding corresponding proteins (Chen et al., 2016). Some estimates suggest that at least 13% of all circRNAs have m6A modifications, indicating that a large number of circRNAs could be translated into proteins in ways that have not yet been explored (Yang et al., 2017) (Fig. 2D).

circRNAs can exert regulatory functions outside the cell via the exosome pathway

Exosomes are currently a major area of research and are mainly formed through the process of plasma membrane bilayer invagination and the creation of intracellular multivesicular bodies (MVBs) containing intraluminal vesicles (ILVs). Exosomes are involved in intercellular communication, and their specific roles depend mainly on the bioactives they contain (Kalluri & LeBleu, 2020). Recent studies have shown that circRNAs not only play regulatory roles within cells but can also be transported to the extracellular space via the exosomal pathway to influence the function of target cells (Zhang et al., 2022). circRNAs can regulate tumour proliferation, migration, and invasion via exosomes (Shang et al., 2020); participate in regulating cellular gene expression and differentiation via exosomes (Mao et al., 2021); and contribute to immune function through exosomal regulation. For instance, circNEIL3 can promote macrophage infiltration chemotaxis in the glioma microenvironment (Pan et al., 2022). In conclusion, the circRNA-exosome pathway constitutes a highly intricate system that plays crucial biological roles in both intracellular and intercellular communication. Through the study of the association between circRNAs and exosomes, the detection of the composition and content of circRNAs in exosomes can be used as an indicator to predict the stage of disease progression and patient prognosis (Fig. 2E).

Glioblastoma

Glioblastoma (GBM) is the most common primary highly aggressive malignant tumour of the central nervous system (Velásquez et al., 2019). The prognosis for patients with GBM is often poor, with data showing that the median survival time is only 12–18 months, and the five-year survival rate is only approximately 13.8% after active treatment (Ghaemi et al., 2022; Witthayanuwat et al., 2018). Therefore, the search for new biomarkers is essential for identifying therapeutic targets and early diagnostic markers that may greatly improve patient prognosis.

Abnormal metabolism is an important cancer marker, and abnormal glycolysis and intracellular signalling play crucial roles in cancer proliferation, migration, and invasion (Park, Pyun & Park, 2020). Li et al. (2021b) reported that circHECTD1 was highly expressed in GBM cells and that it interacted with miR-320-5p to inhibit its expression. Additionally, solute carrier family 2 member 1 (SLC2A1) was identified as a direct downstream target of miR-320-5p, and its expression was suppressed by miR-320-5p. However, CircHECTD1 upregulates SLC2A1 expression by inhibiting the expression of miR-320-5p. SLC2A1, also known as glucose transporter protein 1 (GLUT1), plays a crucial role in glycolysis and is highly expressed in various cancers, including liver, lung, colorectal, and breast cancers, promoting the proliferation and migration of cancerous cells (Liu et al., 2022; Zheng et al., 2022).

In addition, Li et al. (2021a) discovered that circHECTD1 was highly expressed in GBM tissues but expressed at low levels in normal tissues. CircHECTD1 expression was also positively correlated with the Karnofsky scores of patients, indicating that upregulated circHECTD1 expression is associated with a poor prognosis. Animal experiments also demonstrated that knockdown of circHECTD1 inhibited GBM growth in mice. Overexpression of circHECTD1 indirectly upregulated solute carrier family 10 member 7 (SLC10A7) expression by suppressing miR-296-3p expression through miRNA sponge action. SLC10A7 is a cytokine that belongs to the solute carrier family SLC10 and regulates intracellular calcium signalling. It also has regulatory effects on various cellular processes, such as cell proliferation, growth, and gene expression (Berridge, Bootman & Roderick, 2003; Durin et al., 2022; Karakus et al., 2020). Li et al. (2021a) also demonstrated that overexpression of SLC10A7 could reverse the inhibitory effect of circHECTD1 knockdown on GBM.

Further research has revealed that various circRNAs possess protein-coding functions (Chen & Sarnow, 1995). In their most recent study, Ruan et al. (2023) reported that a variant of circHECTD1, known as hsa_circ_0002301, has a protein-coding function. The functional peptide 463aa encoded by this gene was identified using LC-MS/MS. The RNA-binding protein RBMS3, which has been implicated in the regulation of various biological processes such as apoptosis, gene transcription, and cell cycle progression (Penkov et al., 2000), can specifically bind to the flanking intron sequence of hsa_circ_0002301. This interaction induces the formation of hsa_circ_0002301. Ruan et al. (2023) analysed the 463aa peptide sequence and found that it contains a ubiquitination-associated structural domain. This domain promotes the degradation of NR2F1 by regulating the ubiquitination of the K396 site of NR2F1. This site can directly bind to the promoter regions of vasculogenic mimicry (VM)-associated proteins (MMP2, MMP9, and VE-cadherin), thereby enhancing GBM VM. Furthermore, hsa_circ_0002301 and 463aa significantly inhibited the proliferation, migration, invasion, and tubular structure formation of GBM cells, as well as VM formation in vitro and in vivo. This study sheds light on a novel pathway in which the RBMS3-induced circHECTD1-encoded functional peptide 463aa mediates the ubiquitination of NR2F1, thereby inhibiting VM in GBM.

In conclusion, circHECTD1 can lead to abnormal cell metabolism and promote the development of GBM through the miR-320-5p/SLC2A1 and miR-296-3p/SLC10A7 axes. Conversely, the variant hsa_circ_0002301 encodes a functional peptide 463aa, which inhibits the proliferation, migration, invasion, tube formation, and VM of GBM in vitro and in vivo, thereby improving the prognosis of patients with GBM. These studies indicate that circHECTD1 plays a crucial regulatory role in GBM and provides potential targets for developing new treatment strategies. However, these findings need to be validated in larger samples and further research is required to determine the clinical application value of these discoveries.

Gastric carcinoma

Gastric cancer (GC) is a prevalent malignancy of the digestive system and ranks among the top five most commonly diagnosed cancers worldwide. Its estimated annual incidence surpasses 1 million new cases (Smyth et al., 2020). Nevertheless, GC has become a significant global health issue due to its high mortality rate attributable to late detection, tumour drug resistance, and other factors (Petryszyn, Chapelle & Matysiak-Budnik, 2020; Schinzari et al., 2014). Hence, exploring novel biomarkers and investigating mechanisms of drug resistance could offer new strategies and targets for treating GC.

Drug resistance is a significant hurdle in cancer treatment (Wu et al., 2014). Studies have reported the association of circRNAs with the development of drug resistance in cancer (Chen et al., 2021). Diosbulbin-B (DB), a diterpenoid with antitumour activity, is hepatotoxic at high concentrations (Wang et al., 2014). Therefore, increasing tumour sensitivity to DB can effectively improve its therapeutic effect while reducing liver damage. To address this issue, Lu et al. (2021) found that inhibiting circHECTD1 led to restricted tumour growth, an increased proportion of GC cells stalled in the G0/G1 phase by DB and a significant decrease in the median lethal dose (LD50) of DB in GC cells. circHECTD1 indirectly upregulates pre-B-cell leukaemia homeobox 3 (PBX3) via competitive inhibition of miR-137, and overexpression of PBX3 increases drug resistance in gastric cancer cells to DB. PBX3 belongs to the pre-B-cell leukaemia family and has been reported to play crucial roles in various cancers such as acute myeloid leukaemia, gastric cancer, colorectal cancer, and hepatocellular carcinoma (Morgan & Pandha, 2020). Cai et al. (2019) conducted a study that revealed significantly higher expression levels of circHECTD1 in gastric cancer tissues than in normal tissues. Multivariate survival analysis revealed that patients with high circHECTD1 expression had significantly shorter overall survival than those with low expression, indicating that increased circHECTD1 expression is linked to poor prognosis. Moreover, overexpression of circHECTD1 inhibited miR-1256, leading to the upregulation of USP5 and activation of the β-catenin/c-MYC signalling pathway, thus promoting glutamine catabolism. Conversely, knockdown of circHECTD1 reduced β-catenin/c-MYC signalling pathway activation and decreased glutamine catabolism. The c-MYC gene family plays a crucial role in regulating the expression of thousands of genes directly or indirectly, and its products are frequently found to be activators in human cancers (Dhanasekaran et al., 2022). In contrast, a high rate of glutamine consumption is a common metabolic feature of cancer (Márquez et al., 2017).

While in vitro experiments have demonstrated the ability of circHECTD1 to enhance the resistance of GC cells to DB through the miR-137/PBX3 pathway and promote cancer development via the miR-1256/USP5 pathway, further in vivo experiments are necessary to confirm its impact on DB resistance. Inhibiting circHECTD1 not only enhances chemotherapy efficacy but also reduces cancer cell proliferation and metabolism, indicating its potential as a future therapeutic target.

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a type of primary liver cancer that constitutes approximately 90% of such cases (Dimitroulis et al., 2017; Forner, Reig & Bruix, 2018). According to global cancer statistics, HCC ranks as the fourth most common cancer and the sixth leading cause of cancer-related deaths (Villanueva, 2019). HCC is known for its aggressive nature and high susceptibility to metastasis. Unfortunately, it is often identified in later stages due to a lack of specific early symptoms and effective diagnostic markers, which leads to a poor prognosis (Ge & Huang, 2015). Thus, the identification of potential biomarkers for HCC is critical for improving the diagnosis and treatment of this disease.

Numerous studies have demonstrated that circRNAs are involved in regulating various malignant biological processes in HCC by utilizing a diverse array of pathways, including competitive inhibition of endogenous RNA (Li et al., 2020a), binding to RNA-binding proteins (Liu et al., 2020) and exosomal pathways (Huang et al., 2020). For instance, a study conducted by Jiang et al. (2020) revealed that circHECTD1 upregulated MUC1 through competitive inhibition of miR-485-5p. Subsequent qRT-PCR analyses confirmed that MUC1 expression was notably greater in HCC tissues than in normal tissues. Additionally, Kaplan–Meier survival curves suggested that patients with high MUC1 expression exhibited substantially shorter survival times than those with low MUC1 expression, suggesting that elevated MUC1 expression indicates a poor prognosis for individuals diagnosed with HCC. Moreover, recent studies have indicated that miR-485-5p functions as an oncogene, playing significant roles in the pathogenesis of multiple types of cancer such as glioma (Cheng et al., 2021), hepatocellular carcinoma (Zhao et al., 2022), and lung adenocarcinoma (Chen, Wu & Bao, 2023), and is also implicated in disease progression associated with distinct degenerative disorders, such as osteoporosis (Zhang et al., 2018b) and Alzheimer’s disease (He et al., 2021b).

It is evident that circHECTD1 plays a role in the pathophysiology of hepatocellular carcinoma by regulating the miR-485-5p/MUC1 network. Although the lack of in vivo experiments limits the conclusions of the study, it cannot be denied that this represents a promising therapeutic target and prognostic indicator for HCC. Furthermore, the observed inhibitory effect of circHECTD1 on miR-485-5p suggests its potential involvement in the pathogenesis of other cancers and the modulation of certain degenerative diseases in humans. However, due to current limitations in research, further investigation is necessary, with immense potential for future studies.

Acute ischaemic stroke

Acute ischaemic stroke (AIS) is one of the major types of strokes. AIS is more common than haemorrhagic stroke and can cause significant disability or even death in patients (Campbell et al., 2019). The goal of treatment is to prevent irreversible nerve damage. Currently, recombinant tissue-type plasminogen activator (rtPA) reperfusion is the only FDA-approved treatment modality for acute ischaemic stroke. While new treatment modalities such as stem cell therapy are being explored, effective options remain limited (Barthels & Das, 2020; Paul & Candelario-Jalil, 2021). Many patients therefore endure long-term disability because they do not receive optimal treatment within the appropriate time frame (Li, Tang & Yang, 2021d). As a result, exploring new therapeutic targets and diagnostic markers is essential. Peng et al. (2019) conducted a study comparing patients with AIS with normal controls and found a positive correlation between circHECTD1 expression and disease severity in patients with AIS. Additionally, Kaplan–Meier survival curve analysis revealed that patients with high circHECTD1 expression had significantly shorter survival than those with low circHECTD1 expression. Patients with high circHECTD1 expression also had a significantly greater probability of recurrence than did those with low circHECTD1 expression. These findings suggest that increased expression of circHECTD1 is a poor prognostic indicator for patients with AIS. Additionally, Han et al. (2018) reported that circHECTD1 expression was significantly greater in the plasma of patients with AIS than in that of normal controls. They also found that knockdown of circHECTD1 reduced the extent of brain infarct injury in mice. In addition, they observed decreased expression of glial fibrillary acidic protein (GFAP), which suggests that circHECTD1 is involved in astrocyte activation. Astrocytes are been considered passive cells that provide support to neurons, but in recent years, astrocytes have been shown to play an important role in nerve injury and repair (Bugiani et al., 2022). Han et al. (2018) demonstrated by FISH experiments and immunofluorescence assays that circHECTD1 competitively inhibits miR-142 upregulation of TIPARP to promote astrocyte autophagy, which in turn promotes astrocyte activation. Zhang, He & Wang (2021) reported that the expression of circHECTD1 was elevated in HT22 cells after treatment with oxygen–glucose deprivation/reperfusion (OGD-R). circHECTD1 upregulates follistatin-like 1 (FSTL1) by acting as a sponge for miR-27a-3p, which is involved in OGD-R-induced neuronal cell injury. Many studies have demonstrated that FSTL1 participates in tissue remodelling and inflammatory processes, mediating cell–matrix interface interactions and contributing to various fibrotic and autoimmune diseases (Li et al., 2021c). Conversely, He et al. (2022) discovered that circHECTD1 acted as a sponge for miR-355 to indirectly upregulate notch receptor 2(NOTCH2) and promote endothelial-mesenchymal transition (EndMT) in human cerebral microvascular endothelial cells (HCMECs). Knocking down CircHECTD1 inhibited EndMT and facilitated migration and tube-formation in OGD-R-treated HCMECs.

Studies suggest that circHECTD1 may play roles in astrogliosis and EndMT in AIS through the miR-142/TIPARP and miR-355/NOTCH2 axes, respectively. It can also contribute to neuronal cell injury via the miR-27a-3p/FSTL1 axis. The primary source of experimental research samples was patient plasma, which may not directly reflect changes in the site of the lesion, leading to potential bias in the results. The reliability of the experiment can be further proven by examining the patient’s cerebrospinal fluid. However, peripheral blood can indirectly reflect changes at lesion sites, demonstrating the significant potential of circHECTD1 as a biomarker for evaluating disease severity and prognosis.

Silicosis

Silicosis is a pulmonary fibrosis disease that is mainly caused by progressive fibrotic changes in the lungs as a result of long-term exposure to an environment containing high levels of free silica dust. A serious and common occupational disease (Leung, Yu & Chen, 2012; Steenland & Ward, 2014), Silicosis starts with the phagocytosis of silica crystals by alveolar macrophages (Tan & Chen, 2021). Subsequently, silica-induced apoptosis of macrophages triggers a chain reaction of inflammatory responses that ultimately induces fibroblast activation and leads to lung fibrosis (Hu et al., 2006). Currently, there is a lack of effective diagnostic methods for detecting silicosis before it progresses to an advanced stage (Austin, James & Tessier, 2021). There are also only a limited number of drugs available to slow disease progression, and therapeutic options remain ineffective (Adamcakova & Mokra, 2021; Wang et al., 2022). As a result, there is an urgent need to identify potential therapeutic targets for silicosis to develop effective treatments for this disease.

According to a study by Zhou et al. (2018), circHECTD1 was highly expressed in RAW264.7 cells exposed to SiO2. Furthermore, circHECTD1 regulated the ubiquitination of HECTD1/ZC3H12A, which resulted in the activation of alveolar macrophages. Additionally, exposure to SiO2 upregulated HECTD1, which promoted the activation and migration of human pulmonary fibroblasts from adults (HPF-a). Chu et al. (2019) conducted further research into the relationship between circHECTD1/HECTD1 and HPF-a, building upon the study by Zhou et al. (2018). As per their findings, under SiO2 exposure, circHECTD1 indirectly promoted the proliferation and migratory capacity of HPF-a, reduced apoptosis, and promoted cellular autophagy through the upregulation of HECTD1 expression in both HPF-a and patient cells. Numerous studies have indicated that cellular autophagy involves not only a “garbage can” but also a dynamic recycling system. In some instances, autophagy can function as an energy generator. It has also been demonstrated that autophagy is linked to the activation of HPF-a migration (Mizushima & Komatsu, 2011; Zhu et al., 2016). Fang et al. (2018) reported contrasting findings that SiO2 exposure elevated circHECTD1 expression while suppressing HECTD1 protein expression, and promoted EndMT in mouse endothelial cells. It has been demonstrated that epithelial–mesenchymal transition (EMT) and EndMT in epithelial and endothelial cells, caused by various factors, are significant contributors to fibroblast and extracellular matrix (ECM) accumulation leading to the development of fibrotic disease (Wynn, 2008).

In conclusion, circHECTD1 has dual roles in the development of pulmonary fibrosis. While it indirectly promotes the activation of AMOs and modulates the function of HPF-a by upregulating the HECTD1/ZC3H12A axis, it can also promote EndMT in lung endothelial cells and contribute to lung fibrosis. These studies did not further investigate the specific mechanism by which circHECTD1 promotes EndMT. Subsequent research can build upon this foundation, but it is undeniable that circHECTD1 plays a crucial regulatory role in promoting pulmonary fibrosis.

Acute lung injury

Acute lung injury (ALI), also known as mild or moderate acute respiratory distress syndrome (ARDS), is a disease characterized by diffuse alveolar injury with disruption of the epithelial-endothelial barrier caused by direct or indirect injurious factors (Butt, Kurdowska & Allen, 2016). ALI is associated with high morbidity and mortality (Mowery, Terzian & Nelson, 2020). Currently, nonpharmacological treatment for ALI mainly involves lung-protective mechanical ventilation as there are no specific drug therapies available (Mokrá, 2020). Therefore, there is an urgent need to explore molecularly targeted therapeutic agents for ALI to reduce its high morbidity and mortality.

As research on molecular pathophysiology has advanced, increasing evidence suggests that circRNAs play a significant regulatory role in the repair of damage in ALI (Cao et al., 2022). According to a study by Li et al. (2022a), there was a marked reduction in the expression of circHECTD1 in human and mouse alveolar epithelial cells (AECs) stimulated with lipopolysaccharide (LPS). However, the overexpression of circHECTD1 has been found to upregulate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and sirtuin 1 (SIRT1) indirectly by acting as a sponge for miR-320a and miR-136. Notably PIK3CA is involved in numerous cellular processes such as angiogenesis, survival, metabolism, and proliferation (Canaud et al., 2021), while SIRT1 is a highly conserved NAD-dependent deacetylase with anti-inflammatory and antioxidant properties that can help mitigate tissue damage caused by inflammation (Yang et al., 2022). (Li et al., 2022a) discovered that overexpression of circHECTD1 inhibited the programmed cell death of AECs.

In summary, circHECTD1 can activate both the miR-320a/PIK3CA and miR-136/SIRT1 pathways in LPS-induced ALI, promoting cell proliferation and metabolism while also preventing further cell damage caused by inflammation and slowing AECs apoptosis. A thorough study of the mechanisms underlying the effects of circHECTD1 on ALI could be tremendously helpful in understanding and preventing the progression of ALI to ARDS, as well as developing targeted therapies for ALI.

Ulcerative colitis

Ulcerative colitis (UC) is a diffuse and chronic inflammatory disease that primarily affects the superficial mucosa of the rectum and colon, causing mucous bleeding. UC is characterized by various clinical manifestations, with acute UC episodes potentially leading to toxic megacolonitis, while long-term chronic UC may increase the risk of cancer development (Danese & Fiocchi, 2011; Ordás et al., 2012). Unfortunately, there are currently no drugs that can completely cure UC (Wehkamp & Stange, 2018). The primary objective of treating UC is to prevent its recurrence and induce remission of active UC (Adams & Bornemann, 2013). Furthermore, the global incidence and prevalence of UC have shown increasing trends over the years (Ungaro et al., 2017). Therefore, it is crucial and pressing to investigate the underlying causes of UC and uncover new potential therapeutic targets.

Currently, with the progress of molecular biology research, there is growing evidence suggesting that circRNAs play a role in the progression and regression of UC via miRNA/mRNA networks (Xu et al., 2022a). Xu et al. (2022b) reported that the expression of circHECTD1 was lower in UC tissues than in normal tissues. They also found that circHECTD1 could indirectly upregulate human antigen R (HuR) by acting as an miRNA sponge, which reduced the secretion of inflammatory factors such as IL-1 α, IL-1 β, and IL-6, and increased the expression of autophagy-related genes such as ATG5 and ATG9. These findings suggested that circHECTD1 may mitigate the inflammatory response in UC through cellular autophagy. Interestingly, many studies have demonstrated that circRNAs often act as oncogenes in cancer, promoting the development of various types of cancer (Sang et al., 2019). However, in UC, circRNAs act by promoting cellular autophagy to alleviate the inflammatory response associated with the disease (Xu et al., 2022b).

Indeed, the aetiology of UC remains unclear and may result from various factors, including genetics, immune abnormalities, and dysbiosis of the intestinal flora (Du & Ha, 2020). The relationship between reduced circHECTD1 expression and UC has provided new insights for investigating the pathogenesis of this disease. In vivo and in vitro experiments have demonstrated that circHECTD1 can effectively alleviate the development of UC. However, these findings require validation in larger samples and further research to determine the clinical utility of these discoveries.

Atherosclerosis

Cardiovascular disease is responsible for more global deaths than any other disease, making it the number one cause of mortality worldwide. Atherosclerosis (AS) is a significant pathological change that can lead to cardiovascular disease (Herrington et al., 2016). Numerous studies have demonstrated that the collagen produced by leukocytes and vascular smooth muscle cells (VSMCs) as they move towards the intima serves as the primary origin of the fibrous cap (FC) and plays a crucial role in preserving plaque stability (Miano, Fisher & Majesky, 2021). Autophagy and apoptosis of VSMCs can adversely impact the stability of the FC and contribute to the formation of necrotic foci, ultimately resulting in plaque rupture (Grootaert et al., 2018). Consequently, identifying a biological target that can enhance VSMC proliferation and reduce VSMC apoptosis is crucial. This may serve as a significant therapeutic approach for treating and slowing the progression of AS.

A study by Feng et al. (2023) revealed that the expression of circHECTD1 was elevated in VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB). They found that circHECTD1 enhanced the stability of EZH2 mRNA and increased the expression of EZH2 protein through an interaction with the RNA-binding protein KHDRBS3. This mechanism promoted VSMC proliferation and migration while inhibiting apoptosis. Indeed, elevated levels of EZH2 can disrupt the normal patterns of histone modifications, resulting in abnormal epigenetic regulation and contributing to tumour development (Hanaki & Shimada, 2021). Breast cancer (Li et al., 2020b), gastric cancer (Pan et al., 2016), prostate cancer (Park et al., 2021), and numerous other types of cancer are specifically associated with these aberrations caused by overexpressed EZH2. In summary, circHECTD1 enhances the proliferation and inhibits the apoptosis of VSMCs via the KHDRBS3/EZH2 axis. Consequently, it represents a potential biomarker for assessing prognosis and treating AS. However, it is important to note that circHECTD1 has dual effects. While EZH2 increases expression, which delays AS progression, the overexpression of EZH2 itself has been associated with cancer development.

Myocardial ischaemia–reperfusion injury

When acute myocardial infarction (AMI) occurs, early revascularization of the infarct-related coronary artery is important for preventing further deterioration of the AMI. However, during reperfusion therapy, there is a risk of myocardial ischaemia-reperfusion injury (MIRI), which can result in secondary damage to the heart (Samsky et al., 2021; Zhao et al., 2021). Previous studies have indicated that factors such as inflammation, the release of reactive oxygen species, and local microvascular occlusion play crucial roles in the development of MIRI (Li, Sun & Li, 2019b). Therefore, targeted interventions aimed at controlling inflammation and reducing the release of reactive oxygen species can effectively decrease the likelihood of MIRI during reperfusion. Recent studies have demonstrated the critical regulatory roles of ncRNAs in cardiovascular diseases, including MIRI (Marinescu et al., 2022). In a study conducted by Yang et al. (2023), they observed heightened expression of a specific ncRNA known as circHECTD1 in a mouse model of MIRI, particularly in ischaemic tissues. Their findings indicated that circHECTD1 increased the expression of ROCK2 in cells by functioning as an miR-138-5p sponge, consequently fostering inflammatory responses. ROCK2 is a serine/threonine kinase, and research has indicated that increased levels of ROCK2 in cardiovascular diseases can lead to oxidative stress and enhance inflammatory responses, thus exacerbating cardiovascular injury (Shimokawa, Sunamura & Satoh, 2016). In the MIRI model, downregulation of circHECTD1 resulted in decreased expression of ROCK2, as well as reduced production and release of proinflammatory factors such as TNF- α, IL-6, and IL-1 β (Yang et al., 2023).

Based on these findings, it can be concluded that circHECTD1 plays a role in regulating the cellular inflammatory response through the miR-138-5p/ROCK2 axis in the MIRI model, contributing to the development and exacerbation of MIRI. Treatment targeting circHECTD1 holds promise for reducing the occurrence of MIRI and preventing secondary damage in patients with AMI, potentially improving overall treatment outcomes. However, further research and clinical studies are needed to fully explore the therapeutic potential of circHECTD1 in the context of MIRI.

Hypertrophic scars

Hypertrophic scars (HS) are characterized by an excessive and prolonged response to dermal injury, resulting in fibrous tissue overgrowth. They typically occur as a result of damage to the reticular dermis and aberrant wound healing processes. Various factors can contribute to the development of HS, including trauma, burns, surgical incisions, vaccinations, skin piercings, acne, and herpes zoster infections (Lee & Jang, 2018; Ogawa, 2017). Previous studies have demonstrated that persistent activation of the TGF- β/SMAD signalling pathway is a significant factor in abnormal wound healing and scars formation (Zhang et al., 2020). Therefore, investigating biomolecular markers that regulate the excessive activation of the TGF- β/SMAD signalling pathway could help reduce scar formation.

Recent studies in the field of epigenetics have revealed that aberrant circRNA expression has a reversible impact on various biological behaviours of fibroblasts by affecting epigenetic mechanisms (Lv et al., 2020). Ge et al. (2022) reported significantly elevated levels of circHECTD1 expression in scar tissue compared to normal tissue. The presence of circHECTD1 indirectly enhances the TGF- β/SMAD signalling pathway through the miR-142-3p/HMGB1 pathway, resulting in increased human skin fibroblast (HSF) proliferation, migration, and fibrosis. These processes subsequently contribute to abnormal wound healing and scar formation. Recent studies have indicated that increased expression of transforming growth factor β (TGF- β) can result in metabolic and functional impairments while also promoting the progression of epithelial–mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition. These effects ultimately contribute to the development of fibrosis (Peng et al., 2022). SMAD transcription factors function as crucial mediators of TGF- β signalling. Moreover, according to existing studies, it is suggested that the phosphorylation of the SMAD-linked region itself serves as a signalling pathway (Kamato et al., 2020).

In summary, circHECTD1 promotes HS formation primarily by activating the TGF- β/SMAD signalling pathway through the miR-142-3p/HMGB1 axis. However, the sample size of the study was small, which may have led to bias. Therefore, the generalizability of these findings needs to be validated in a larger sample.