While SARS-CoV-2 may resist viral RNA identification, evade retinoic acid-inducible I-like receptor (RLR) signaling, and decrease IFN production through its own proteins such as NSP5, NSP6, NSP7, and ORF9b (Beyer and Forero, 2022), IFN plays a crucial role in the antiviral response. Additionally, viruses like influenza frequently make use of lncRNAs that do not require interferon activation to boost their reproduction through several molecular pathways involved in the integrity of the viral genome and replication machinery. Due to the strong resemblance between SARS-CoV and SARS-CoV-2, it has been demonstrated that the influenza virus and SARS-CoV exhibit comparable expression patterns in the lung tissue of infected mice (Hartshorn, 2020). We hazard a guess that SARS-CoV-2 may also hijack lncRNAs to control ISGs, RIG-I, JAK-STAT, NF-κB, and other pathways to increase replication and infection.

The expression of lncRNA-CMPK2, which is involved in the control of ISGs, is elevated in SARS-CoV-2 infection. With ISGs, lncRNA-CMPK2 aids in directing transcriptional repressors or chromatin-modifying factors to sites in a subset of ISGs. This results in a block to transcription or the induction of a repressive chromatin state in these regions, downregulating the IFN response (Kambara et al., 2014). In addition, in SARS-CoV-2 infected cells, through the utilization of NF-κB, RIG-I detection of viruses causes an increase in EGOT expression levels, which in turn causes the expression of several ISGs (GBP1, ISG15, Mx1, BST2, ISG56, IFI6 and IFITM1) to be downregulated (Carnero et al., 2016).

Although their precise mechanisms are unknown, lncRNAs such as DANCR, TUG1, and Gm26917 are engaged in the control of the RIG-I pathway. It is possible that the process of LncATV and Lnc-Lsm3b might serve as a guide for the investigation of these lncRNAs’ mechanisms. For instance, LncATV binds and inhibits RIG-I-mediated innate immune activation (Fan et al., 2019). Lsm3b’s GA-rich sequence produces a double-stranded RNA stem-loop structure that competitively binds to the C-terminal domain of RIG-I, stabilizing the contact between the RIG-I caspase recruitment domain (CARD) and helicase domain, keeping it in an auto-repressed conformation (Bird, 2018). In addition, RIG-I is kept in an inactive state by Lsm3b, which also effectively suppressed the dsRNA-induced ATPase activity of RIG-I and disturbed TRIM25-mediated K63-linked ubiquitination of RIG-I upon viral infection (Jiang et al., 2018).

The human interferon responses are also thought to be negatively regulated by the lncRNA LUCAT1 (Agarwal et al., 2020). Due to its major effect on the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, it can limit the expression of STAT targets, reduce the generation of interferon, and eventually encourage the infection and replication of the SARS-CoV-2 virus.

On the other hand, lncRNA Lethe induced by inflammatory factors TNF-α and IL-1β binds to NF-κB to inhibit Rela DNA binding and target gene activation (Rapicavoli et al., 2013), reducing the release of inflammatory factors with anti-infective effects may be the potential mechanisms of lncRNA-assisted SARS-CoV-2 immune evasion.

The study of lncRNAs in SARS-CoV-2 immune evasion is lacking, and its mechanisms of innate immune evasion are primarily extrapolated from other viruses. While the mechanisms of lncRNA in humoral immunity are less well understood, Only Agirre et al. demonstrated that lncRNAs regulate essential genes during B-cell immune activation (Agirre et al., 2019). There is no evidence that lncRNAs play a role in the humoral immune evasion mechanisms of SARS-CoV-2.

Type II alveolar epithelial cells that have been infected by SARS-CoV-2 undergo apoptosis and cytokinesis, which kills the cells. Additionally, it activates lung macrophages and causes the release of pro-inflammatory cytokines and chemokines, which tends to the M1 phenotype (Morris et al., 2020). In conclusion, SARS-CoV-2 infection triggers the inflammatory cascade response in humans, and the ensuing unchecked inflammatory factors finally result in a cytokine storm, which has devastating outcomes including ARDS and systemic multi-organ failure.

22 lncRNAs with the ability to target the 10 cytokines overexpressed in the COVID-19 cytokine storm were found by Morenikeji et al., eight of which target two or more cytokines (Morenikeji et al., 2021). For instance, NORAD specifically targets five crucial cytokines (IL-6, IL-10, CSF3, CXCL10, and TNF-α), and its possible mechanisms may be the involvement of the NF-κB signaling pathway through the miR-552-39/MYD88 axis in TNF-α induced apoptosis, inflammatory, and oxidative stress (Lei et al., 2022), which in turn leads to an increase in multiple cytokines. RAD51-AS1 targets three significant cytokines (IL-6, TNF-α, CCL2), and its possible mechanisms may express in response to cellular damage from viral replication within macrophages in SARS-CoV-2 infection, leading to the expression of pro-inflammatory cytokines (Morenikeji et al., 2021). In addition, RAD51-AS1 was discovered to be associated with the NF-κB pathway in inflammatory bowel disease (Papoutsopoulou and Campbell, 2021), which could account for the upregulation expression of IL-6, TNF-α, and CCL2. GAS5 targets two crucial cytokines (IL-10 and TNF-α), and the possible mechanisms may be that upregulating GAS5 expression decreases miR-223-3p expression, which increases NLRP3 expression levels and promotes pyroptosis (Mo et al., 2022). GAS5 also downregulates miR-23a-3p levels, which can inhibit the release of inflammatory substrates by inhibiting the TLR4/TNF-α/IL-10 signaling pathway (Gao and Huang, 2021).

NEAT1 and MALAT1 target more than 95% of the genes and proteins among the many differential expression lncRNAs (Laha et al., 2021) and are essential for the development of cytokine storms. By attaching to pro-caspase-1 and encouraging the activation of NLRP3, NLRC4, and AIM2 inflammasomes, NEAT1 enhances caspase-1 activation, cytokine production, and pyroptosis (Zhang P. et al., 2019). Through the absorption of miR-3076-3p and reduction of the latter function to control the expression of NLRP3 (Zhang M. et al., 2019). Additionally, upregulated NEAT1 competitively binds Let-7a and releases TLR4 from it, activating TLR4 and stimulating downstream signaling (Zhang and Niu, 2019). NEAT1 as well as competitively binds miR-1246 and releases NAKP, which mediates TNF-α and IL-1 induced NF-κB activation and severe inflammatory response, causing a serious inflammatory reaction (Bai et al., 2018). MALAT1 also suppresses the creation of NLRP3 inflammasomes by sponging miR-23C, preventing its repressive impact on the target gene ELAV1, which is the upstream gene of the NLRP3 inflammasome (Li et al., 2017). Additionally, MALAT1 functions as a molecular sponge for miR-146a, lowering miR-146a levels to lessen its inhibition of the generation of inflammatory responses induced by LPS (Dai et al., 2018). In addition to interacting with miRNAs, MALAT1 also binds to E2H2, which in ER-negative breast cancer works as a coactivator of RelA and RelB and upregulates the production of NF-κB targeted genes including IL-6 (Lee et al., 2011). In addition to the aforementioned, it can stimulate neutrophil chemotaxis by controlling p300-dependent IL-8 (Wei et al., 2019).

MiRNAs may be an important antiviral tool (Trobaugh and Klimstra, 2017), which can regulate the innate and adaptive immune systems (Ambros, 2001; Trobaugh and Klimstra, 2017) and can also cause silencing or degradation of viral group genes by directly binding them. How miRNAs resist SARS-CoV-2 may be mainly of two types: regulation of ACE2 and TMPRSS2 expression and direct binding to the viral genome to silence or degrade it.

Although miRNAs have antiviral effects, some miRNAs can also evade the host’s antiviral response through other pathways to ensure their spread and achieve the effect of immune escape. SARS-CoV-2 creates an environment in which the virus can reproduce in host cells by affecting the expression levels of host genes (Barbu et al., 2020). It can be mainly divided into two types of mechanisms: interference of host miRNA and mutation of viral genome binding sites.

The infection process of SARS-CoV-2 is mainly divided into two clinical phases, a viral infection of target cells and tissues and a state of severe inflammation (Pascarella et al., 2020). Inflammatory responses such as cytokine storms are caused by pro-inflammatory genes such as IL-6, IL-8, IL-1ß, NF-kB, and STAT3 (Hirano and Murakami, 2020). It is well known that miRNAs are deeply involved in the regulation of cytokine expression (Palanisamy et al., 2012). A large number of miRNAs can regulate the expression of IL-1β, IL-6, and IL-8, and studies have shown that there are a large number of miRNA binding sites in the 3′UTR of IL-1β, IL-6, and IL-8 mRNA (Chou et al., 2018).

Multiple miRNAs are thought to play pro-inflammatory roles in the immune factor storm of SARS-CoV-2. A study confirmed that miR-155 expression is significantly elevated in COVID-19 patients and demonstrates that elevated miR-155 leads to elevated levels of pro-inflammatory cytokines (Soni et al., 2020). Another bioinformatics study identified 10 miRNAs that may play a role in triggering cytokine storms, among which miR-155-5p is one of the 10 identified miRNAs. They may regulate the expression of multiple signaling pathways including IL-2, NF-κB, and MAPK, and trigger the inflammatory response in SARS-CoV-2 (Chow and Salmena, 2020). Following the same pathway we found that another study identified miR-8066, miR-5197-3p, miR-4778-3p, and miR-6864-5p sequences in the SARS-CoV-2 genome. These SARS-CoV-2-mediated miRNAs alterations may act as autocrine or paracrine agonists in host cells to trigger pro-inflammatory cytokines due to increased NF-κB activity (Hirabara et al., 2022). Another study found that miR-146a, miR-21, and miR-142 also trigger inflammation through the activation of MAPK and NF-κB signaling in SARS-CoV-2 patients (Tang et al., 2020). Continuing investigations along miRNAs found that multiple studies have suggested that downregulation of miR-21 and miR-142, which target pro-inflammatory genes, will promote multiple cascade reactions and the activation of JAK-STAT cell signaling pathways, which have the effect of pro-inflammatory and aggravating diseases (Bai and Bian, 2022; Panda et al., 2022).

In addition to this, several other mechanisms play a role in cytokine storms. A KEGG pathway analysis revealed the involvement of the miR-320 family (miR-320a, miR-320b, and miR-320c) in the regulation of the TGF-β signaling pathway and adhesion junctions, which may be related to pro-inflammation and could also be considered relevant to the severity of SARS-CoV-2 (Cavalli et al., 2021). In a study by Giuliani et al., both miR-320b and miR-483-3p/5p, which may both target glucose/lipid metabolism and IGF1 gene expression, were found to be upregulated in mortality cases compared to survivors. And the findings suggest that their serum levels were elevated by 20% and were associated with a threefold increased risk of death during hospitalization in SARS-CoV-2 patients (Giuliani et al., 2022). Besides, Wilson et al. found that severe disease was associated with higher levels of IL6, IL10, IL22, CXCL10, CCL2, and CCL20 and lower levels of miR-495-3p, miR-451a, and miR-29b-3p. Both the CCL20/IL6/IL10/miR-451a model and the 3miRNA/11CC model established in this study provide some clues to reveal the developmental pattern of SARS-CoV-2 (Wilson et al., 2022).

There are also alterations in the expression of miRNAs whose pro-inflammatory mechanisms are not fully understood that have been suggested in several studies to be associated with the development of uncontrolled inflammation in SARS-CoV-2 patients. One study demonstrated that dysregulation of miR-1207-5p during infection may be responsible for the uncontrolled inflammation that occurs in most severe SARS-CoV-2 cases (Bertolazzi et al., 2020). In contrast, miR-618 was shown to be more expressed in SARS-CoV-2 patients than in healthy controls in a study by Li et al. They suggested that the differential expression of miR-618 was associated with immune dysfunction (Li C. et al., 2020).

Except for the regulation of immune factors, in the SARS-CoV-2 cytokine storm, the binding of SARS-CoV-2 stinger protein to the ACE2 receptor, followed by ACE/Ang II/AT1R axis activation, causes IL-6/STAT hyperactivation of the NF-κB axis (Mahmudpour et al., 2020). Simultaneous activation of NF-κB and STAT-3 enhances the NF-κB activation mechanism (IL-6 amplifier) (Murakami and Hirano, 2012). Cytokine storm can be triggered by excessive IL-6 activation in lung tissue (Chi et al., 2020). A computer study showed that upregulation of six host miRNAs targeting ACE2 and TMPRSS2 (miR-32-5p, miR-98-3p, miR-214-3p, miR-421, miR-423-3p and miR-1246) may cause a severe inflammatory response associated with causing severe SARS-CoV-2 (Calderon-Dominguez et al., 2022).

Not only host miRNAs can cause cytokine storms, but also SARS-CoV-2 miRNAs can play the same role. SARS-CoV-2-derived miR-147-3p may enhance TMPRSS2 expression (Liu et al., 2021). And six SARS-CoV-2 miRNAs targeting immune genes (SARS-CoV-miR-1-5p, SARS- CoV-miR-2-5p, SARS-CoV-miR-3-5p, SARS-CoV-miR-4-5p, SARS-CoV-miR-5-5p, and SARS-CoV-miR-6-5p) were discovered Target immune-related genes that play important roles in immune pathways such as TNF and chemokine signaling pathways (Satyam et al., 2021).

RT-PCR and SARS-CoV-2 antigen detection kits are now commonly used to detect the presence of SARS-CoV-2 infection (Jalandra et al., 2020). Rodrigues et al. found that lncRNA NEAT1 and MALAT1 were differentially expressed in saliva and nasopharyngeal swabs from SARS-CoV-2 positive and negative patients, with NEAT1 predominantly in saliva samples expression was upregulated and MALAT1 expression was upregulated in nasopharyngeal samples (Rodrigues et al., 2021). In a study by Martínez-Fleta et al. comparing the differential expression miRNAs in SARS-CoV-2 infection and community-acquired pneumonia, multivariate analysis displayed a combination of four miRNAs (miR-106-5p, miR-221-3p, miR-25-3p, and miR-30a-5p) that discriminated between both pathologies (Martínez-Fleta et al., 2022). Barbagallo et al. discovered that Circ-3205 was exclusively expressed in positive samples and that its level was strongly linked with the level of viral Spike mRNA, thus demonstrating the biomarker function of circRNAs (Barbagallo et al., 2022). NcRNAs appear to be used to detect some sequelae or complications in addition to the presence of infection. For instance, the study of Sabetian et al. demonstrated that lncRNAs can also be used as an early diagnostic biomarker for male infertility/reproductive disorders caused by SARS-CoV-2 (Sabetian et al., 2021), assisting patients in receiving treatment sooner.

Zhong et al. showed that the lncRNAs expression profile may identify between severe and non-severe COVID-19 cases, as well as between healthy people and infected patients (Zhong et al., 2022). Measurement of expression of the lncRNAs levels may help predict and monitor patient treatment, according to research by Badr et al. that found A2M-AS1 and NCBP2AS1-1 to be useful in differentiating between severe and moderate SARS-CoV-2 infections (Badr et al., 2022). Cheng et al. developed a 7-lncRNA panel with a good differential ability between severe and non-severe COVID-19 patients. It is evident that subtype iCluster2 and iCluster3 indicates more severe condition (Cheng et al., 2021). According to Meidert et al.’s discovery that 20 COVID-19 ARDS patients expressed miRNAs differently from COVID-19 pneumonia patients (Meidert et al., 2021), miRNA profiles may also be able to discriminate between severe and non-severe COVID-19 cases. In conclusion, ncRNAs can be employed in the clinic to diagnose SARS-CoV-2 infection, forecast its severity, and provide prompt and effective treatment approaches.

In contrast to conventional techniques of detection, the use of ncRNAs as a diagnostic biomarker can not only determine whether a person is infected with SARS-CoV-2 but also forecast the severity of the infection and the prognosis. The fact that several ncRNAs have been presented as biomarkers for diverse types of malignancies, however, raises doubt about their diagnostic specificity and may be a fatal defect. So it may be more practical to combine them with other clinical and biochemical markers, such as by adding the expression levels of some ncRNAs to the SARS-CoV-2 scoring system and risk classification.

The scientific community currently recognizes vaccination as the most cost-effective method of preventing SARS-CoV-2 infection, but due to the mutation of SARS-CoV-2, numerous studies have found that the current vaccine against the original strain induces poor neutralization of antibodies with Omicron (Hoffmann et al., 2022; Zhang et al., 2022), leading to many cases of breakthrough infections. The goal of current research is to develop a new generation of vaccines or medications against Omicron, and Brevini et al. discovered that ursodeoxycholic acid (UDCA), a medicine with clinical approval, inhibited FXR signaling and decreased FXR activity, which reduced direct binding of FXR to the ACE2 promoter and ultimately downregulated ACE2 expression, which had the effect of suppressing SARS-CoV-2 infection (Brevini et al., 2023). This finding offers an innovative strategy for preventing SARS-CoV-2 infection. Given that miRNAs play a role in controlling the expression of ACE2 and TMPRSS2, using gene editing techniques to control the expression of miRNAs like miR-200c, miR-421, miR-143, and miR-429 may be able to suppress ACE2 and thereby prevent infection.

This preventive approach of suppressing ACE2 expression may have some disadvantages, such as the fact that FXR not only regulates ACE2 expression but also changes the expression of different groups of genes involved in BA homeostasis, lipid metabolism, and glucose balance. However, the use of gene editing of ncRNAs expression levels may be more targeted and less likely to produce additional side effects. In addition, long-term ACE2 deficiency may also result in the development of hypertension (Burrell et al., 2004). Therefore, this strategy for avoiding viral infection only be effective in the short term, and the application of reversible gene editing techniques may be able to overcome the problem.

One of the key pathogenic mechanisms of SARS-CoV-2 infection is the detrimental influence of unregulated cytokines on the body, and inhibiting elements like IL-6 and NLRP3 inflammasomes may be a feasible treatment approach. As was already demonstrated, IL-6 and NLRP3 vesicles can be regulated by MALAT1 and NEAT1, and the use of IL-6 and NLRP3 blockers such as tolimumab and glibenclamide can lower morbidity and death (Paniri and Akhavan-Niaki, 2020). Gasparello et al. reported that the release of key proteins of the COVID-19 “cytokine storm” can be inhibited by mimicking the biological activity of miRNAs, and their study showed that transfection with miR-93-5p agomiR can downregulate SARS-CoV-2 S protein-induced IL-8 (Gasparello et al., 2021). According to Pfafenrot et al., these AS-circRNAs combined with short-circRNA could successfully target the 5′-UTP complex of SARS-CoV-2, limit the genomic expression of SARS-CoV-2, and 90% decrease viral replication in cell culture. Additionally, it was shown that functional antisense activity was invariably higher in the circRNAs backbone when comparing the generation of antisense sequences in circRNAs with that of linear RNA. As a result, AS-circRNA is a powerful and cutting-edge molecular strategy for regulating and targeting various RNAs (Pfafenrot et al., 2021). Direct regulation of ncRNAs by nanoparticles/CRISPR/EV may also be an effective therapy. However, due to the complexity of the ncRNAs interaction network and the fact that only a balanced and appropriate immune response facilitates the elimination of the virus, a thorough understanding of its particular action mechanisms network is essential.

By 30 April 2023, at least one in ten people would have been infected with SARS-CoV-2 globally, according to WHO statistics. SARS-CoV-2 infection has been shown to have a variety of effects, including affecting respiratory, cardiovascular and hematological, neurological, and mental health, as well as the function of the endocrine and reproductive systems, which were previously thought to be transient in most SARS-CoV-2 infection sequelae in healthy young adults (Willi et al., 2021). According to another review, there are several potential late complications, including pulmonary fibrosis, atherothrombosis, stroke, and diabetes (Desai et al., 2022). The various complications and sequelae associated with SARS-CoV-2 infection significantly increase the burden on society, consume more medical resources, and hamper social advancement. Since we are likely to experience a continuous SARS-CoV-2 infection wave in the future, understanding the role of ncRNAs in this process is crucial.

Although the precise mechanisms causing COVID-19 long-term complications are still unknown, there is a growing amount of research suggesting that ncRNAs are involved. The presence of SARS-CoV-2 in cerebrospinal fluid has also been confirmed (Zhou et al., 2020). Approximately 40% of the lncRNAs discovered to date are specifically expressed in the brain (Harrow et al., 2012), and differential lncRNAs play an important role in neuronal, lung cancer, and various diseases (Wu et al., 2021). This evidence may show that lncRNAs play a role in COVID-19-induced neurological sequelae. Su et al. summarized the ncRNAs mechanisms in pulmonary fibrosis, such as overexpression of miR-142-5p and downregulation of miR-130a-3p expression leading to sustained pro-fibrotic effects of macrophages (Su et al., 2015). CircRNA TADA2A suppresses lung fibroblasts via miR-526b/Cav1 activation and lowers lung fibroblast proliferation via miR-203/CaV2 (Li J. et al., 2020).

Regular vaccination to maintain the potency and titer of neutralizing antibodies in our bodies has become an important method of preventing infection while we adjust to the wave of SARS-CoV-2 infection and accept the impact of its complications and sequelae. Tschumper et al. discovered that RNA-seq was able to distinguish specific expression profiles across the continuum of B cell differentiation into PCs, and confirmed that ncRNA plays a crucial role in B cell differentiation (Tschumper et al., 2022).