miRNAs are a class of small, non-coding RNA molecules typically 18–25 nucleotides in length that play essential roles in the post-transcriptional regulation of gene expression. miRNAs function by binding to complementary sequences in the 3′ untranslated regions (3′ UTRs) of target messenger RNAs (mRNAs). This results in the degradation or translational repression of the target mRNAs (O’Brien et al., 2018; Bahojb Mahdavi et al., 2025).

miRNAs not only regulate cellular signaling but, also play a critical role during viral replication (Bannazadeh Baghi et al., 2024; Bahojb Mahdavi et al., 2025). They affect viral replication by targeting either viral genome and/or by modulating the host immune responses (Table 1). Viral miRNAs aid in virus replication by targeting genes involved in host immune response mechanisms (Liao et al., 2021b; Bannazadeh Baghi et al., 2024; Bahojb Mahdavi et al., 2025). Conversely, the host-derived miRNAs can directly suppress viral RNAs or modulate host response mechanisms. For example, miR-22 has been reported to promote HCV replication by binding to 5UTR of HCV (Kunden et al., 2020). Similarly, miR-210 and miR-199a-3p have been reported to inhibit Hepatitis B Virus (HBV) (Zhang et al., 2010). During Japanese encephalitis virus (JEV) infection, expression of RNF11 is regulated by miR-19b-3p, which results in modulation of antiviral immune responses (Zhu et al., 2015). Recently, miR-98-5p has been identified as a potential suppressor of SARS-CoV-2 replication (Rizkita and Astuti, 2021). On the other hand, miR-146a modulates TRAF6 and promotes IAV replication (Yan et al., 2025). Similarly, miR-373 facilitates viral replication during HSV-1 infection (Dass et al., 2023). miRNA-mediated regulation of neuroinflammation has also been reported during HSV-1 infection (Xie et al., 2018b; Patrycy et al., 2022). During ZIKV infection, miRNAs also modulate host immune responses and fetal development (Carvalho-Silva et al., 2022; Lai et al., 2025). DENV is another arbovirus like ZIKV, which interacts with host miRNAs to regulate host-pathogen interactions. For instance, miR-4488 contributes to cellular immune responses during DENV infection and may serve as a potential biomarker (Filip et al., 2025).

miRNAs can modulate the host immune responses in diversified ways, from expression regulation of pro-inflammatory cytokines to influencing the activity of pattern recognition receptors (PPRs). For example, during viral infection, miR-155 is upregulated, resulting in enhanced interferon production and stronger TH1 responses (Arroyo et al., 2020). Interestingly, miR-146 plays a dual role during viral infection. It can behave as pro-viral or anti-viral, depending upon the context (Nahand et al., 2020). Recently, Chen and colleagues have reported that miR-155 disrupts the mitochondrial homeostasis and regulates interferon responses (Chen et al., 2023). Another miRNA, miR-29, regulates IFN-γ production and Th1 cell development by suppressing T-bet and Eomes (Steiner et al., 2011). Moreover, miR-150 and miR-223 have been reported to attenuate STAT1 signaling in T cells (Moles et al., 2015). Another study highlights that miR-126-5p negatively regulates host antiviral immune responses (Wang et al., 2022).

RNA-based therapeutics, for example, miRNA mimics and inhibitors, may offer unique opportunities to combat viral infections. They target either host immune responses or virus-specific molecular pathways. One such example is Miravirsen, which is the inaugural miRNA anti-HCV therapeutic. It functions by inhibiting miR-122, which is a proviral miRNA (Brillante et al., 2024). Research is being conducted to explore the potential of miRNA-based antiviral therapies. For instance, miR-122 mimics are being studied for their potential to suppress HBV replication (Mahmoudian-Sani et al., 2019). Additionally, circulating miR-122 has also emerged as a potential biomarker for liver infection, especially in case of HCV infection (Ullah et al., 2022). Similarly, miR-199A-3p is being investigated as a potential therapeutic for HBV. Additionally, anti-miR-210 is being researched to stop cancer-causing effects in liver diseases related to HBV (Zhang et al., 2010).

Studies have shown that viruses can alter host miRNA expression profiles and understanding these miRNA-virus interactions may offer a basis for miRNA-based diagnostic and therapeutic tools. For instance, altered miRNA expression profiles have been observed during SARS-CoV-2 infection. Some host-derived miRNAs were found to be specifically depleted during SARS-CoV-2 infection (Bartoszewski et al., 2020). On the contrary, certain miRNAs are upregulated and contribute towards inflammation and lung injury during viral infection. Targeting these host-virus-miRNAs interactions can result in novel therapeutics.

Circulating miRNAs are stable in serum and can also serve as diagnostic biomarkers. During DENV infection, miR-150 expression levels have been reported to correlate with disease severity (Chen et al., 2014). Wong and colleagues have recently reported that miR-21-5p, miR-146a-5p, miR-590-5p, miR-188-5p and miR-152-3p can be used to detect DENV infection (Wong et al., 2020). Furthermore, miRNA profile in correlation with COVID-19 disease severity has also been reported (Pius-Sadowska et al., 2025). Collectively, these findings indicate the promising potential of miRNA-based therapeutics and diagnostics as new approaches against viral infections.

lncRNAs are RNA molecules longer than two hundred nucleotides. They do not code for proteins; however, they play important roles in gene regulation at transcriptional and post-transcriptional levels. Increasing evidence suggests that lncRNAs play important roles during viral infection (Liu et al., 2019a; Statello et al., 2021). Certain lncRNAs enhance viral replication or alter the host cell environment to facilitate viral pathogenesis, whereas others may alter interferon signaling to block infection and support viral clearance. Their wide range of functions indicates that lncRNAs can serve as important candidates for diagnostic and therapeutic applications (Liu et al., 2019a; Aldweik et al., 2025).

lncRNAs have recently been identified as key regulators of the innate immune system and cellular defenses against viral infections. Rather than encoding proteins, these molecules function as modulators that influence key immune signaling pathways, including NF-κB, IRF3 and JAK/STAT. By interacting with transcription factors, chromatin modifiers and RNA-binding proteins, lncRNAs determine whether viral infections are effectively recognized and eliminated or allowed to persist in the host (Table 2). For example, interferon-inducible lncRNAs such as USP30-AS1, NRAV, TSPOAP1-AS1, lnc-MxA and lnc-Lsm3b play pivotal roles in fine-tuning interferon signaling and host antiviral immune responses during IAV infection (Wang and Cen, 2020; Wang et al., 2022; Cao et al., 2025). Similarly, IVRPIE enhances host defense against the influenza A virus by upregulating IFN-β1 and key ISGs through histone modification (Zhao et al., 2020). Another lncRNA#32 promotes type I IFN signaling and ISG expression, thereby restricting EMCV, HBV and HCV replication (Nishitsuji et al., 2016). lncRNA IFITM4P stabilizes IFITM1/2/3 expression by sponging miR-24-3p, which results in increased innate antiviral responses (Xiao et al., 2021).

Numerous lncRNAs have been documented to enhance viral propagation by inhibiting host immune responses. For instance, lncRNA-BTX enhances viral replication by modulating the localization of RNA-binding proteins DHX9 and ILF3 (Cao et al., 2023). Recently, Yan and colleagues have reported that lncRNA-DRNR disrupts the STAT1 activation. This disruption results in the reduced IFN-β mediated antiviral responses (Yan et al., 2024). Another lncRNA, THRIL, has been reported to inhibit IRF3 activation. This inhibition results in a reduction in type I and III interferons and enhanced IAV replication (Chen et al., 2025).

Moreover, several studies have also reported the integral roles of lncRNAs in various host signaling pathways. For example, lncRNA-ACOD1 interacts with GOT2 enzyme, which facilitates viral replication (Wang et al., 2017b). Another lncRNA, HEAL, interacts with FUS protein during HIV infection and facilitates HIV transcription (Chao et al., 2019). A recent study suggests that EBV-BART lncRNAs regulate the host gene expression (Verhoeven et al., 2019).

Many lncRNAs have been reported to display expression patterns that correlate with the stage and often severity of viral infection. In recent studies, specific lncRNA expression patterns were observed during influenza and SARS-CoV-2 infections, which can aid in early diagnosis of these viral infections (Van Solingen et al., 2022; Aldweik et al., 2025). High-throughput sequencing has also revealed several differentially expressed lncRNAs during viral infections. In a study, a group of seven lncRNAs has been developed to effectively differentiate between severe and non-severe cases of COVID-19 (Cheng et al., 2021). Another study has also reported that lncRNAs such as HOTAIRM1, PVT1 and AL392172.1 are important regulators of SARS-CoV-2 infection (Moazzam-Jazi et al., 2021). Furthermore, studies conducted with EV71 and DENV have also reported that lncRNAs are associated with immune responses (Wang et al., 2017c; Li et al., 2018). Similarly, during ZIKV infection, altered expression of lncRNAs in neuroprogenitor cells has also been observed (Venkatesan et al., 2022). Recently, Arslan and colleagues have reported that lncRNAs such as ERCP FER1L4 and LOC1100133669 can be used as potential biomarkers to determine the disease severity during CCHFV-mediated infection (Arslan et al., 2022). Taken together, these findings indicate that lncRNAs can be used as novel tools not only to identify viral infection, but also to assess the severity of the disease. However, developing a standardized method to detect and quantify lncRNAs is an open venue, requiring further research.

Similar to diagnostic, therapeutic potential of lncRNAs is also being studied. Several studies have reported both pro- and anti-viral lncRNAs. For example, lncRNA-ACOD1 has been reported to be upregulated during several viral infections, indicating its potential pro-viral activity (Wang et al., 2017b). Moreover, research is being carried out to target virus encoded lncRNAs to determine their use in antiviral therapies. For instance, EBV sisRNAs or KSHV PAN RNA have been targeted to assess the impacts on viral latency and immune clearance (Min et al., 2022; Media et al., 2025).

Moreover, altering certain host-derived lncRNAs expression profiles can aid in the reversal of virus latency and possible approach for eradicating chronic infections (Kulkarni et al., 2023). Current research is focused on optimizing delivery mechanisms, such as lipid nanoparticles and plant-derived exosomes, for the administration of synthetic lncRNAs or CRISPR modulators (Kazemian et al., 2022; Hillman, 2023).

circRNAs are noncoding RNA without a 5′-cap structure or 3′ poly(A) tail. Their 3′ and 5′ ends are covalently bonded, forming a closed circular shape. circRNAs are generated from viral genome transcription/splicing or from host cell gene splicing. These ncRNAs play an important role in regulating host immune responses and viral replication (Belousova et al., 2018; Panda, 2018; Maarouf et al., 2023; Wang et al., 2024).

Recent evidence shows that circRNAs can regulate viral replication by acting as competitive endogenous RNAs (ceRNAs) (Table 3). For example, in Hantaan virus infection, circ_0000479 was shown to sponge miR-149-5p, thereby lifting miR-149-5p suppression of RIG-I, which likely enhances antiviral defense (Lu et al., 2020; Yin et al., 2024). In another study with MERS-CoV, knockdown of host circRNAs (e.g., circFNDC3B, circCNOT1) led to significantly reduced viral load, consistent with a ceRNA-based regulatory mechanism (Zhang et al., 2020). Host circRNAs can act as miRNA sponges during viral infection, binding intracellular miRNAs to block their activity and modulate host gene expression, ultimately creating conditions favorable for viral replication. circRNAs–miRNAs interactions are vital in HBV-related hepatocellular carcinoma (HCC). Rui Liao and colleagues studied circRNA_101764, circRNA_100338, circ-ARL3 and circ-ATP5H in HBV-HCC, showing their roles in tumor development and metastasis (Liao et al., 2021a). circRNAs appear to play important roles in virus-induced immune responses. Li and colleagues have recently performed genome-wide sequencing of brain tissues from Japanese encephalitis virus (JEV)-infected mice. This study has revealed the altered expression of circRNA hsa_circ_0000220 (Li et al., 2020b). Which acts like a sponge for miR-326-3p, leading to an increase in cytokine production. Recent studies also indicate that disruptions in ceRNA networks, which involve lncRNAs, circRNAs and ncRNAs, play significant roles in the pathogenesis of SARS-CoV-2 (Aghajani Mir, 2024).

circRNAs can also alter essential cellular pathways by modulating protein stability, phosphorylation and ubiquitination. For instance, host-derived circ_0001400 binds to splicing factor PNISR and downregulates the KSHV gene expression. This results in aversion of apoptosis and development of latency (Tagawa et al., 2023). During IAV infection, the host-derived circVAMP3 disrupts the NP-polymerase interactions as circVAMP3 acts as a decoy for viral nucleoprotein (NP) and non-structural protein 1 (NS1). This interference restores interferon-β production and suppresses viral replication (Min et al., 2023). Together, these findings indicate that circRNA–protein interactions influence both viral pathogenesis and host immune responses. During EV-A71 infection, hsa_circ_0045431 binds hsa_miR-584, forming the circRNAs/NLRP3 axis that activates pyroptosis (Hu et al., 2023). Similarly, hsa_circ_0007321, derived from the DIS3L2 gene, has been reported to play an important role during ZIKV infection.

This circRNA, which is derived from the host, was shown to regulate the viral replication pathway by sponging miR-492. This, in turn, affects the protein NFKBID, which is a negative regulator of the NF-κB pathway (Kang et al., 2023).

In another interesting study, purified circRNAs were introduced into HeLa cells to observe their effect. They seemed to trigger a strong immune response, which was also demonstrated by increased expression of antiviral genes such as RIG-I, PKR, MDA5 and OAS1. As expected, this made the cells more resistant to viral infection and lower infection rates were observed in subsequent assays (Chen et al., 2017; Liu and Chen, 2022).

Due to their covalently closed structure, circRNAs are highly stable in serum samples, rendering them ideal candidates for the novel diagnostic tools. Moreover, as they are key regulators of immune responses against viral infections, they are being investigated for potential targets for therapeutic interventions. It has recently been reported that CRISPR techniques can be utilized to knock out circRNAs and their role inside different cellular pathways can be further studied (Santer et al., 2019; Yin et al., 2024). A recent study has also reported that circRNAs can be used to diagnose HBV infection (Jiang et al., 2020). Similarly, another circRNA, circ_3205, can aid in the COVID-19 diagnosis. Moreover, circ_3205 is a virus-encoded ncRNA, which also acts as a has-miR-298 sponge and positively regulates SARS-CoV-2 infection (Barbagallo et al., 2022).

Not only are circRNAs highly stable, but they also trigger strong immune responses, making them ideal candidates for RNA-based vaccine platforms. Recently, a study has investigated a potential circRNA vaccine encoding receptor binding domain (RBD) of SARS-CoV-2. This vaccine elicited robust T-cell responses, which may provide broad protection against different variants (e.g., Delta and Omicron) of SARS-CoV-2 (Qu et al., 2022). Amaya and colleagues have further explored the potential of circRNA vaccine in murine tumor models and their study revealed effective CD8+ T cell responses by dendritic cells (Amaya et al., 2023). Initially, scientists were struggling with the circularization techniques; however, with emerging research in synthetic biology, novel circularization techniques are being developed to synthesize circular RNA (Abe et al., 2018). Progress in molecular virology and host immunology, along with synthetic biology, has greatly improved our understanding of ncRNAs-mediated host-pathogen interactions, paving the way for improved diagnostics and therapeutics.