The role of dsRNA A-to-I editing catalyzed by ADAR family enzymes in the pathogeneses

ABSTRACT

The process of adenosine deaminase (ADAR)-catalyzed double-stranded RNA (dsRNA) Adenosine-to-Inosine (A-to-I) editing is essential for the correction of pathogenic mutagenesis, as well as the regulation of gene expression and protein function in mammals. The significance of dsRNA A-to-I editing in disease development and occurrence is explored using inferential statistics and cluster analyses to investigate the enzymes involved in dsRNA editing that can catalyze editing sites across multiple biomarkers. This editing process, which occurs in coding or non-coding regions, has the potential to activate abnormal signalling pathways that contributes to disease pathogenesis. Notably, the ADAR family enzymes play a crucial role in initiating the editing process. ADAR1 is upregulated in most diseases as an oncogene during tumorigenesis, whereas ADAR2 typically acts as a tumour suppressor. Furthermore, this review also provides an overview of small molecular inhibitors that disrupt the expression of ADAR enzymes. These inhibitors not only counteract tumorigenicity but also alleviate autoimmune disorders, neurological neurodegenerative symptoms, and metabolic diseases associated with aberrant dsRNA A-to-I editing processes. In summary, this comprehensive review offers detailed insights into the involvement of dsRNA A-to-I editing in disease pathogenesis and highlights the potential therapeutic roles for related small molecular inhibitors. These scientific findings will undoubtedly contribute to the advancement of personalized medicine based on dsRNA A-to-I editing.

GRAPHICAL ABSTRACT

The process of dsRNA A-to-I editing can regulate the pathogenesis of a wide range of diseases. In our manuscript, we have summarized and reviewed the underlying mechanisms behind its action.

1. Introduction

The process of RNA editing is widely recognized as a post-transcriptional mechanism for RNA processing, which induces modifications in the nucleotide sequence of the encoded RNA within each gene. This intricate process encompasses nucleotide insertion or deletion, along with nucleobase deamination [1–3]. The eukaryotic RNA transcriptome frequently undergoes various types of post-transcriptional RNA modifications. Unlike DNA, RNA editing provides the ability for tunability and reversibility [4]. Moreover, it does not result in permanent changes to the genome, ensuring enhanced security and leveraging efficient delivery of genetic information. Recent studies have emphasized the pivotal role of RNA editors in disease progression. Adenosine-to-Inosine (A-to-I) RNA editing represents a significant mechanism for epigenetic modification and is the most prevalent type of RNA modification observed in mammals [5]. The catalytic process involves the action of adenosine deaminase (ADAR) on double-stranded RNAs (dsRNAs), which are specifically recognized by a family of enzymes known as ADARs [1]. The process can enzymatically convert the adenosine base within an RNA molecule to an inosine (guanine) base, potentially leading to genetic disorders during the delivery or transmission of genetic information. (Figure 1A) [6]. The process of dsRNA A-to-I editing enhances the diversity of transcriptome and proteome specifically, while maintaining the integrity of the genome sequence [7]. Meanwhile, it can also exert an impact on various aspects, encompassing RNA splicing, translation, exportation, localization, stability, and biogenesis of non-coding RNAs such as miRNAs and circular RNAs [8–10]. The alterations in the targeted gene sequence for editing may disrupt the formation of correlated dsRNA structures, resulting in heterogeneous translational production. Moreover, it can impact the interaction between transcriptomes and other molecules, thereby influencing their regulatory functions. Due to its pivotal role in ageing, growth, development, and pathogenesis processes; dsRNA A-to-I editing contributes to a wide range of consequences spanning from single nucleotide mutations to genome-wide genetic alterations [11]. The subsequent section provides a comprehensive summary and analysis of the pathogeneses involved or induced by this process, thereby emphasizing its indispensable roles in therapeutic treatments for related diseases.

Figure 1.

The biosynthesis process of dsRNA A-to-I transformation. (A) The ADAR enzymes facilitate the enzymatic conversion of adenosine base to inosine (guanine) base, thereby effecting the transformation of adenosine into inosine within the dsRNA molecule. (B) The ADAR family of proteins exhibit distinct domain structures, consisting of varying numbers of dsRNA-binding domains and catalytic deaminase domains. Notably, two isomers of ADAR1 (p110 and p150), represented by different shades of purple coloration in gene structures, possess distinctive Z-DNA binding domains. Specifically, ADAR1p150 contains two Z-DNA binding domains (Zα, Zβ) at the N-terminus while ADAR1p110 has one Z-DNA binding domain (Zβ) located close to the N-terminus within its gene structure. Furthermore, ADAR3 encompasses an arginine-rich domain highlighted in green.

2. dsRNA A-to-I editing and the ADAR enzyme

2.1. ADAR enzyme

The process of dsRNA A-to-I editing is primarily catalyzed by enzymes belonging to the ADAR family. As illustrated in Table 1, the key members of the ADAR family encompass ADAR1, ADAR2 (ADARB1), and ADAR3 (ADARB2) (Figure 1B). The enzyme variant of ADAR1 consists of two common transcriptome members: ADAR1p150 and ADAR1p110. Similarly, ADAR2 has two subtype variants: ADAR2a (ADAR2S) and ADAR2b (ADAR2L) [12]. Both ADAR1 and ADAR2 are widely expressed in various human tissues for the recognition and catalysis of dsRNA editing. However, unlike other members, ADAR3 is predominantly expressed in the human brain without exhibiting deaminase activity [13]. ADAR1 is primarily responsible for editing repetitive sequences, while ADAR2 is accountable for modifying the coding region of mRNA. In contrast, ADAR3 inhibits the activity of both ADAR1 and ADAR2 by segregating their respective substrates [14]. The deficiency of ADAR1 in mice lasts for approximately one week, during which a significant number of mice exhibit severe phenotypes such as neuronal apoptosis, erythropoiesis defects, and congenital immune response abnormalities [15]. The survival of newborn mice lacking ADAR2 is limited to three weeks after the occurrence of recurrent epilepsy, which is characterized by neuronal death due to excessive influx of Ca²⁺ (attributed to insufficient GluA2 Q/R site editing caused by the absence of ADAR2). However, incorporating the GluA2 Q/R site at the genomic level can rescue the lethal phenotype resulting from ADAR2 deficiency [16,17]. In contrast to the phenotypes observed in mice lacking ADAR1 or ADAR2, each of the ADAR3-deficient mice (C57BL/6N) exhibits an increase in anxiety levels, respiratory distress dependent on hippocampal function, and impairment in long-term memory formation [18].

Table 1.

ADAR1, ADAR2 and ADAR3 and their connections.

ADAR	Subtype	Intracellular Localization	Expression Site	Missing Consequences	Differences in Gene Structure	Interact	References
ADAR1	ADAR1 p150	Nucleus and Cytoplasm	Most Human Tissues	Hematopoietic Deficiency; Embryonic Lethality	ADAR1 has a Z-DNA Binding Domain on the N-terminal Side and An Arginine Rich Domain on ADAR2 and ADAR3.	Competitive Antagonism of ADAR3 with ADAR1 and ADAR2 Inhibits dsRNA Editing from A to I.	[19] [20] [14] [12] [21] [81] [18]
	ADAR1 p110	Nucleus
ADAR2	ADAR2a	Nucleus (Nucleolus)	Brain, Heart, Lung, Liver and Kidney	Epilepsy
	ADAR2b
ADAR3	N/A	N/A	Brain	Anxious; Impaired Memory

2.2. dsRNA A-to-I editing and other RNA modifications

Until now, more than hundreds of RNA modifications have been discovered [22]. Among them, certain modifications with a high occurrence rate are particularly significant, such as N6-adenosine methylation (m⁶A), cytosine hydroxylation (m⁵C), N1-adenosine methylation (m¹A), N7-methylguanosine methylation (m⁷G), N4-acetylcytidine (ac⁴C), and RNA pseudo adenylation. Aberrations in the expression or function of enzymes involved in RNA modifications can give rise to various disorders, including tumorigenesis, neurological and neurodegenerative symptoms, as well as embryonic growth retardation. For example, m⁶A modification is typically regulated by methyltransferases (METTL3, METTL14, METTL16, WATP) and demethylases (FTO, ALKBH5). The complex formed by methyltransferases METTL3 and METTL14 plays a tumor-inhibitory role in endometrial carcinoma. Mutations in METTL14 or down-regulation of METTL3 lead to reduced levels of m⁶A methylation. These alterations contribute to increased proliferation and tumorigenicity of endometrial cancer through activation of the AKT pathway [23]. The m⁶A eraser enzyme FTO facilitates melanoma tumorigenesis and confers resistance to immunotherapy by actively transporting m⁶A into mRNA, thereby augmenting its stability [24]. Further investigations have revealed that A-to-I editing and m⁶A can interact by modulating the expression of their key enzymes. For instance, ADAR1 interacts with METTL3 to facilitate the proliferation, migration, and invasion of breast carcinoma (BC) via the ADAR1-METTL3-YTHDF1 axis. Additionally, loss of ADAR1 impedes BC growth while simultaneously limiting METTL3 and ARHGAP5 in vivo; thus establishing an ADAR1-METTL3 axis as a novel pathway linking dsRNA A-to-I editing with m⁶A RNA modification during the progression of BC deterioration [25].

The occurrence of base substitutions for dsRNA editing extends to non-coding regions as well. There are numerous modifications in the activities of RNA bases in some non-coding RNAs’ transcriptions, including miRNAs [3,26], mRNAs [3,27], siRNAs [3,28], tRNAs [29,30], snRNAs [31], snoRNAs [32], IncRNAs [33], etc. The process of dsRNA A-to-I editing is a dynamic progression that generates diverse transcriptomes, thereby inducing non-synonymous codon changes or splicing events in various RNA species during transcription processes and even disrupting miRNA maturation [34]. The evidence indicates that miRNA-487b A-to-I editing is a selective process occurring at multiple domain sites following ischaemia, and the overexpression of edited miRNA-487b may ultimately promote angiogenesis [35]. The majority of dsRNA A-to-I editing occurs at various sequence sites within the non-coding region of the gene, predominantly affecting miRNAs due to their high recruitment and binding factors in such regions. In comparison to normal melanocytes, ADAR1 is specifically downregulated in metastatic melanoma, resulting in a lack of editing for two specific miRNAs (mir-455-5p and mir-378-3p). This further promotes tumour progression by increasing their transcriptome numbers. [36].

In summary, the process of dsRNA A-to-I editing facilitated by the ADAR family is a crucial step in mature RNA biosynthesis and plays a pivotal role in the onset and progression of various diseases. Consequently, this review will provide an overview of the involvement or induction of pathogenesis through dsRNA A-to-I editing.

3. Disease and dsRNA A-to-I editing

The ADAR enzyme plays a pivotal role in the occurrence and progression of disease by regulating the process of dsRNA A-to-I editing. Initially, ADAR1 impacts specific cellular sensors, subsequently influencing associated or induced pathogenesis. For instance, it can initially bind to dsRNA derived from endogenous retroviral elements (EREs), thereby attenuating its ability to activate host dsRNA sensors. Cellular dsRNA sensors such as MDA-5 and PKR, along with ZBP1, possess the capability to discriminate and eliminate exogenous dsRNA while inducing interferon (IFN) production upon detection of exogenous nucleic acids. The process of ADAR1-mediated A-to-I editing of dsRNA prevents activation of the sensor MDA-5 and PKR [37]. The dsRNA-binding domain is recognized by ADAR1, which effectively inhibits the amplification of immune response mediated by host MDA-5 [38]. Additionally, ADAR1 has been found to inhibit another dsRNA sensor known as PKR. PKR is a cytoplasmic pattern recognition receptor (PRR) that forms dimers, undergoes auto-phosphorylation, and subsequently phosphorylates the eukaryotic initiation factor 2α (eIF2α) upon recognition of dsRNA [39]. Phosphorylation of eIF2α leads to global translation retardation which hampers viral replication. The activation of ZBP1 leads to caspase-8-dependent apoptosis and MLKL-mediated necroptosis in ADAR1-deficient cells [40]. The reason for this is that ZBP1 functions as a sensor for left-handed Z-nucleic acids, while ADAR1 acts as an inhibitor of IFN signalling to protect organisms from disease-associated IFN activation [38,41]. Abnormal expression levels of ADAR1 result in an augmented production of IFNs, which may partially contribute to the enhancement of autoimmunity and the induction of systemic lupus erythematosus (SLE) [42]. The implication is that the process of dsRNA A-to-I editing mediated by ADAR1 is associated with autoimmune diseases.

The significance of dsRNA A-to-I editing in bacterial-viral immunity should be emphasized. Certain viruses produce dsRNA during transcription and replication, leading to a predominant occurrence of A-to-I editing in viral dsRNA intermediates [43,44]. The ADAR1 protein exerts a significant impact on viral immune responses by suppressing the RNA sensing pathways that are orchestrated through the ADAR1-dsRNA-MDA5 axis [43]. ADAR1 can discriminate between endogenous and exogenous dsRNA production during viral infection [38], which serves as a hallmark of antiviral defense. Exogenous dsRNA from viruses is recognized by PRRs and MDA5, major components of the innate immune sensing pathway. MDA5 aggregates on unedited dsRNA and assembles into filaments [45–48]. The activation signals mediated by the mitochondrial antiviral signaling protein result in enhanced phosphorylation of transcription factors IRF3 and IRF7. Subsequently, these transcription factors translocate to the nucleus and promptly induce the expression of IFN and IFN-stimulated genes, thereby eliciting proinflammatory and antiviral responses. The clues presented here demonstrate that ADAR1 can impede the activation of MDA5 and PKR-mediated viral replication [49]. Such phenomena contribute to viral fitness switching, immune evasion, or treatment resistance [50–53]. The knockout of ADAR1 in HeLa cells notably leads to immune activation, which hinders viral replication [54]. The inhibition of ADAR1 could potentially hinder viral replication while simultaneously augmenting the host’s antiviral immune responses.

The process of dsRNA A-to-I editing may exert substantial impacts on neuronal protrusion activity. The AMPA receptor, a subtype of ionotropic glutamate receptors, plays a crucial role in synaptic plasticity in the central nervous system [55]. The mammalian AMPA receptor consists of four sub-units: GluA1, GluA2, GluA3, and GluA4 [56]. Among these subunits, GluA2 is the first to exhibit A-to-I editing sites within its encoded dsRNA sequence domains in mammals [57]. The mRNA transcripts encoding the GluA2 subunit undergo an ADAR2-mediated dsRNA A-to-I editing process that converts the Glutamine codon (Q) to the Arginine codon (R) [58]. This substitution from neutral amino acid residues to positively charged ones significantly reduces Ca²⁺ permeability in the receptor. Notably, GluA2 Q/R site editing plays a critical physiological role in the mammalian central nervous system. Moreover, it serves as a primary target for ADAR2 enzyme activity; failure or prevention of editing at this site facilitates Ca²⁺ influx through AMPA receptors and leads to excitotoxic neuronal necrosis [16,59]. These findings highlight that ADAR2-edited GluA2 Q/R site is an important regulatory target in brain function. The serotonin receptor (5-HT), belonging to GPCRs, is located on cellular surfaces and primarily regulates circadian rhythms, mood, appetite, and sexual behavior. Among 5-HT receptor family members regulated by ADAR enzymes within central nervous system dsRNA molecules is 5-HT2C receptor (5-HT2CR) [60]. Within the pre-mRNA structure of 5-HT2CR receptor gene locus V exon region lies five adenosine residues targeted by ADAR enzymes at sites A to E. Editing at sites A to C specifically involves ADAR1 while D site editing differs [61].

The process of dsRNA A-to-I editing plays a certain role in regulating the proliferation or apoptosis pathways of abnormal cells in multiple diseases. ADAR2 upregulates the level of the cell division cycle 14B (CDC14B) mRNA and inhibits cell cycle progression during the G1/S transition by the effect of CDC14B on the Skp/p27/p21 pathway, and then reduces cell proliferation [62]. Also, as one of the tumor suppressors, bladder cancer-associated protein (BLCAP) inhibits cell proliferation but drives carcinoma apoptosis [63,64]. ADAR2 is the primary editor of BLCAP, specifically increasing cell proliferation by activating the Akt/mTOR signalling pathway or STAT3 [65,66]. JAKs further transduce ligand-binding signals through phosphorylation of STATproteins to influence downstream cytokine function for answering the immune response [67]. Dysregulation of the JAK/STAT signalling pathway may lead to a range of autoimmune diseases, with ADAR1 inactivating or blocking the upstream JAK/STAT pathway via TYK2 inhibition, impairing the self-renewal and stemness of glioblastoma stem cells [68]. Those reflect the process of dsRNA A-to-I editing may intervene in the development of disease through the regulation of this pathway.

The ADAR-catalyzed dsRNA A-to-I editing process has a significant impact on protein expression. ADAR1 can convert Serine (Ser) to Glycine (Gly) by editing AZIN1, which also induces the cytoplasmic translocation of AZIN1 to the nucleus. This translocation leads to more aggressive tumor behavior and has been observed in liver carcinomas [69]. On the other hand, ADAR2 catalyzes dsRNA A-to-I editing in SLC22A3, resulting in the replacement of Asparagine with Aspartic acid. This process is elevated in tumor tissues from familial oesophageal carcinomas, leading to decreased expression of SLC22A3 and restricted metastasis [70]. Notably, no functional differences have been observed between ADAR1 and ADAR2 when they simultaneously catalyze dsRNA A-to-I editing processes in either liver or oesophageal carcinomas. MYC is a consistently upregulated protein found in many tumors. ADAR1 regulates MYC expression through the PI3K/AKT pathway. Aberrant MYC expression has been shown to affect resistance to bromodomain and extra-terminal domain inhibitors in pancreatic cancer (PC). Interestingly, higher levels of ADAR1 expression are positively correlated with resistance to these inhibitors. These findings suggest that combining BET inhibitors with ADAR1 inhibitors holds promise for optimizing treatment outcomes for PC [71]. The PODXL gene encodes a protein that is specifically regulated by ADAR2, which mediates the process of dsRNA A-to-I editing. This editing results in the substitution of Histidine with Arginineat codon 241 of PODXL, leading to a loss-of-function phenotype that neutralizes the tumorigenic capacity of unedited PODXL [72]. Furthermore, mutations in genes encoding ADAR family enzymes may contribute to the occurrence and development of abnormalities related to dsRNA-induced or -involved pathogenesis. Mutations in ADAR1 can cause Z-RNA accumulation and activate the Z-RNA sensor ZBP1, potentially leading to RIPK3-mediated necroptosis [42]. These conditions also play a role in autoimmune diseases such as Aicardi-Goutières syndrome(AGS) and asymmetrical hereditary pigmentation [73].

As previously mentioned, a growing body of evidence consistently demonstrates the correlation between disruptions in human dsRNA editing and aberrant ADAR enzymes with diverse pathogeneses, including tumorigenicity, autoimmune disorders, neurological and neurodegenerative symptoms, as well as metabolic diseases (Table 2, Figure 2). A comprehensive review and summary of these findings is currently underway.

Table 2.

Diseases and dsRNA A-to-I editing.

Diseases	ADAR	Site Position	References
Amyotrophic Lateral Sclerosis (ALS)	ADAR2	GluA2 Q/R Site	[76] [77]
Epilepsy	ADAR2	GluA2 Q/R Site	[84] [59]
Bilateral Striatal Necrosis (BSN)	ADAR1	G1007R、P193A	[85] [87]
Depression and Schizophrenia	ADAR1/ADAR2	5-HT2CR	[15] [89] [93]
Aicardi Goutières Syndrome (AGS)	ADAR1	MDA5、P193A、G1007R	[73] [95]
Rheumatoid Arthritis (RA)	ADAR1	N/A	[99] [100]
Systemic Lupus Erythematosus (SLE)	ADAR1 ADAR2	PDE8A1	[101] [99] [102]
Hepatocellular Carcinoma (HCC)	ADAR1/ADAR2	AZIN1/COPA	[106] [106]
Astrocytoma	ADAR2	GluA2 Q/R site	[112] [113]
Breast Carcinoma (BC)	ADAR1	N/A	[116] [119] [123]
Pancreatic Cancer (PC)	ADAR1	circNEIL3/miR-432-5p/ADAR1	[124]
Gastric Cancer(GC)	ADAR1/ADAR2	PODXL	[72] [125]
Esophageal Squamous Cell Carcinoma (ESCC)	ADAR1/ADAR2	N/A	88+89 [126] [127]
Cervical Carcinoma (CC)	ADAR1	N/A	[65]
Thyroid Carcinoma (THCA)	ADAR1	miR-200b/ZEB1	[129]
Type 2 Diabetes Mellitus (T2DM)	ADAR2	Pancreatic β cells	[131] [133] [132]
Chronic Myeloid Leukemia (CML)	ADAR1	let-7 miRNA	[135] [134] [127] [136] [137] [110]
Dyspigmentation Symmetrical Hereditary (DSH)	ADAR1	N/A	[140] [144]

Figure 2.

Diagram of the relationship between dsRNA A-to-I editing and multiple diseases.

3.1. Neurological & neurodegenerative symptoms

3.1.1. Amyotrophic lateral sclerosis (ALS)

Neurodegenerative diseases are triggered by neuronal necrosis. The elevation in intercellular glutamate concentration leads to the generation of toxic substances in the microenvironment of neurons, thereby inducing neuronal degeneration, senescence, and demise. Glutamate excitotoxicity is closely associated with the onset and progression of numerous neurodegenerative disorders and represents one of the most significant mechanisms contributing to nerve cell death. ALS is a chronic neurodegenerative disease characterized by selective motor neuron necrosis, although most cases occur sporadically [74]. Elevated levels of glutamate have been observed in sporadic ALS cases, suggesting that activation of glutamate-gated ion channels may result in an excessive influx of Ca²⁺ and subsequent neuronal death [75]. The pathogenic role played by dysfunction in dsRNA A-to-I editing at the GluA2 Q/R site due to ADAR2 knockdown has been extensively elucidated in sporadic ALS [76,77]. Kawahara et al. employed a laser micro-cutter to isolate individual motor neurons affected by ALS, and the editing efficiency was determined by assessing the variations in digestion patterns of GluA2 mRNA products nested within the reverse transcriptase polymerase chain reaction. Ultimately, they observed that sporadic ALS patients exhibited fewer A-to-I editing sites in the dsRNA domain sequence encoded by GluA2 compared to healthy volunteers [77]. It is worth noting that GluA2 undergoes A-to-I editing at the Q/R site [57,78], which plays a crucial role in determining the Ca²⁺ permeability of AMPA receptors. ADAR2 is responsible for editing all GluA2 expressed in neurons at this specific site [76]. Furthermore, motor neurons with reduced levels of edited receptors experience enhanced Ca²⁺ influx, potentially leading to significant necrosis [16]. Consequently, reactivating ADAR2 through AMPA receptors or inhibiting excessive Ca²⁺ influx could serve as promising therapeutic strategies for repairing degenerating motor neurons in sporadic ALS patients [79,80].

3.1.2. Epilepsy

Epilepsy, being one of the most prevalent neurological and neurodegenerative disorders characterized by unexplained recurrent seizures [81], is associated with long-term exposure to non-lethal levels of elevated calcium concentrations in neurons, leading to plastic changes and ultimately resulting in the development of epilepsy. The AMPA glutamate receptor plays a crucial role in rapid excitatory nerve transmission [82,83]. Therefore, scientists believe that insufficient editing at the GluA2Q/R site leads to increased Ca²⁺ concentrations, which are responsible for epilepsy. Epilepsy triggers a significant elevation in intracellular Ca²⁺ levels, while impairment of editing at dsRNA sequence sites encoded by GluA2Q/R causes substantial enhancement of Ca²⁺ permeability [59]. Thus, there is a correlation between defects in A-to-I editing at GluA2Q/R encoded dsRNA sites mediated by ADAR2 and susceptibility to epilepsy [59,84]. This implies that reduced GluA2Q/R editing sites mediated by ADAR2 contribute to the onset of epilepsy.

3.1.3. Bilateral striatal necrosis (BSN)

BSN is an inherited dystonic movement disorder associated with cerebral oedema. ADAR1 mutants, such as Pro193Ala, Ile872Thr, and Gly1007Arg, have been identified in patients with confirmed AGS exhibiting the BSN phenotype [85]. These mutants are transmitted in both autosomal dominant and autosomal recessive manners, ultimately resulting in loss-of-function of ADAR1 [85]. Moreover, ADAR1-mutated BSNs are implicated in interferon signaling [85]. Spastic paraplegia is a hereditary neurodegenerative disorder linked to ADAR1 mutants and characterized by axonal degeneration and lower limb spasms [86]. The G1007R and P193A mutants of ADAR1 drive upregulation of interferon in BSN as well as manifestation of spastic paraplegia [87]. ADAR1 mutants interfere with dsRNA A-to-I editing at glutamate receptor Q/R sites in the brain, leading to increased Ca²⁺ influx into neurons [88]. This suggests that ADAR1 May serve as a predisposing factor for genetic degenerative dystonia.

3.1.4. Depression and schizophrenia

Depression is an affective mental disorder characterized by symptoms such as sadness, low self-esteem, inattention, and other related manifestations. The aetiology of behavioral and mental disorders fundamentally involves 5-serotonin signal transduction [89]. In contrast to control subjects, individuals diagnosed with severe depression, schizophrenia, or bipolar disorder did not show any changes in the transcriptional editing efficiencies of 5-HT2CR in the brain frontal cortex [90–92]. Discrepancies exist regarding the editing changes of 5-HT2CR mRNA in suicide victims. Under these conditions, scientists suggest that dsRNA A-to-I editing acts as a homoeostatic mechanism that mitigates the impact of various environmental and genetic factors on neuronal functions [93]. Increasing the number of 5-HT2CR editors may contribute to the treatment of mental illness. Furthermore, rhythm plays a significant role in all aspects of physiology including neural activity. The process of dsRNA A-to-I editing mediated by ADAR2 affects circadian rhythms and regulates rhythmic oscillation levels of mRNA expression. Additionally, ADAR2-deficient mice exhibit complete loss of RNA editing rhythm, short-cycle free running behaviour, and gene expression oscillation [94]. This further indicates that dsRNA A-to-I editing plays a crucial role in regulating circadian rhythms.

3.2. Autoimmune disorders

3.2.1. AGS

Immune diseases arise from dysregulation of immune responses that disrupt the body’s ability to defend against pathogens. AGS is an autosomal dominant autoimmune disorder characterized by cerebral atrophy, leukodystrophy, intracranial calcifications, and chronic cerebrospinal fluid lymphocytosis. ADAR1 mutants contribute to the development of AGS by activating immunoreactivity towards dsRNA or impairing Inosine production following IFN-induced intrinsic function inhibition [73]. Nine identified ADAR1 mutants have been associated with AGS [73,95], namely p. Pro193, Ala.Arg892His, p. Ala870Thr, p. Asp1113His, p. Gly1007Arg, p. Tyr1112Phe, p. Lys999Asn, p. Ile872Thr, and p. Lys359Argfs. Notably, G1007R mutation within the deaminase domain results in a complete loss of enzyme activity in ADAR1 [73]. Furthermore, the p193A missense mutation occurs outside of the deaminase domain. Mutagenesis in the first Z-DNA binding domain of ADAR1 p150’s N-terminal reduces enzyme activity, resulting in an overall discharge of IFN in AGS patients [96]. This suggests that the reduced RNA-editing activity of ADAR1 p150 is likely one reason for AGS pathogenesis. Therefore, targeting corresponding ADAR1 mutation sites may be an effective treatment strategy for Ai-cardi-Goutières syndrome. Additionally, ADAR1-specific knockout mice exhibit embryonic lethality with a type I IFN signature resembling AGS symptoms [38,97], which can be rescued by simultaneous knockdown of the Ifih1 gene encoding MDA5 [17,38,98]. E861A mutant mice are also embryonic lethal and deleting MDA5/MAVS can rescue this lethality while increasing IFN-stimulated gene expression [38,96,98]. All these findings suggest that pathogenesis caused by ADAR1 mutants is most likely mediated through an activated MDA5-sensing pathway and therefore makes ADAR1 a key target for treating AGS.

3.2.2. Rheumatoid arthritis (RA)

The RNA-sequencing dataset analysis reveals a significant upregulation trend of total ADAR1 in the synovium of patients with either early or established RA, particularly the pro-inflammatory isoform ADAR1p150 [99]. The expression of ADAR1p150 and the rates of dsRNA A-to-I editing in repetitive Alu elements are increased in circulating mononuclear cells from patients with active RA. Following 12 weeks of antirheumatic treatment, significant reductions in ADAR1p150 expression and dsRNA A-to-I editing rates are observed in patients who exhibit a favourable clinical response [99]. The correlation between increased dsRNA A-to-I editing and the expression of pro-inflammatory genes implies their potential involvement in chronic inflammation [100]. Although the aberrant expression of ADAR1 May be associated with the pathogenesis of RA, further investigation is still required to elucidate the specific underlying mechanisms.

3.2.3. SLE

The pathogenesis of SLE, a chronic autoimmune disease, is characterized by dysfunctions in the immune effectors of B-lymphocytes and T-lymphocytes [99]. The up-regulation of ADAR1, an interferon-inducible enzyme, in SLE T cells has been discovered [99,101]. ADAR2 selectively targets PDE8A1 as its substrate. Up-regulation of ADAR1 May suppress the function of ADAR2, leading to hypo-editing in the PDE8A1 gene transcriptomes of SLE T cells [102]. The modifications in editing multiple dsRNA sequences contribute to the modulation of gene regulation and immune function in SLE, playing a pivotal role in the initiation and propagation of SLE pathogenesis. Therefore, further investigations are warranted to elucidate the still ambiguous pathogenesis of SLE.

3.2.4. Viral infections

ADAR1-mediated dsRNA A-to-I editing plays a crucial role in various viral infections. For instance, ADAR1 enhances the replication of vesicular stomatitis virus (VSV) by inhibiting the kinase activity of PKR and suppressing eIF-2α phosphorylation, thereby facilitating VSV infection [103,104]. Additionally, knockdown or knockout of ADAR1 leads to a reduction in Zika virus(ZIKV) transcription, translation, and titres. This is attributed to the ability of ADAR1 to restore ZIKV replication by suppressing interferon production and PKR activation [105]. Recent RNA-seq data have been utilized to map RNA-editing sites in the SARS-CoV-2 genome [44]. ADAR signatures have been observed in 91 editing events within viral SARS-CoV-2 dsRNA intermediates. Furthermore, infection with SARS-CoV-2 induces type I and III IFNs in lung cancer cell lines, resulting in the inhibition of viral ssRNA replication but also triggering a cytokine storm that further exacerbates severe COVID-19. This dependence on the MDA5/MAVS/IRF3 axis for IFN induction has been identified as a major cellular sensor of SARSCoV-2 [43]. Additionally, knockdown or knockout of ADAR1 leads to a reduction in ZIKV transcription, translation, and titres. This is attributed to the ability of ADAR1 to restore ZIKV replication by suppressing interferon production and PKR activation.

3.3. Tumorigenicity

3.3.1. Hepatocellular carcinoma (HCC)

HCC exhibits the highest mortality rate among all subtypes of carcinomas worldwide. In contrast to other subtypes, such tumor demonstrates a profound disruption that results in an imbalance in dsRNA A-to-I editing. ADAR1 and ADAR2 modulate this imbalance through their differential expression in HCC compared to non-tumour liver tissues. Approximately 70% of cases exhibit overexpression of both ADAR1 p110 and p150, while half of the cases display downregulation of ADAR2 [106]. The differential expression of ADAR1 and ADAR2 in HCC patients is clinically indicative of a poor prognosis, as their overexpression and downregulation in tumours respectively are associated with adverse outcomes [106]. The differentially expressed ADAR1 and ADAR2 also induce specific editing activities, such as overexpression of AZINI and reduced editing of COPA, which are associated with its pathogenesis of [106,107]. The regulation of COPA editing by ADAR2 inhibits the development of HCC [108]. ADAR1 plays a pivotal role in the editing of AZIN1 [69]. The induction of tumorigenesis and enhancement of invasive capability by AZIN1 are positively correlated with the frequency of ADAR1-mediated editing. AZIN1 editing has been observed in HCC tumorigenesis, resulting in amino acid substitution from Ser to Gly. This recoding event can significantly impact protein function, thereby contributing to the tumor onset and development [69]. Additionally, research has demonstrated an escalation in the frequency of AZIN1 editing throughout the progression of diseases, ranging from cirrhosis and primary liver cancer to advanced carcinoma with recurrence and metastasis [69,109]. Given the oncogenic role played by AZIN1, it represents a promising target for future therapeutic interventions against HCC. Moreover, the upregulation of ADAR1 in HCC patients is associated with an increased risk of liver cirrhosis, postoperative recurrence, and unfavourable prognosis [110]. Therefore, the inhibition of ADAR1 or activation of ADAR2 may potentially mitigate the risk of postoperative recurrence in HCC.

3.3.2. Astrocytoma

Astrocytoma refers to a type of tumour formed by astrocytes, while Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most aggressive malignant tumour with an average survival time of 18 months [111]. The imbalance of ADAR2 plays a pivotal role in the development of cancer. Overexpression of ADAR2 in astrocytoma cell lines leads to reduced cell proliferation and decreased tumour volumes and weights in xenografting nude mice models [62]. The analysis of GBM tissue samples reveals a deficiency in editing at the GluA2Q/R site compared to the control [112]. Ozawa et al. elucidated the causal relationship between inadequate Q/R site editing and malignant astrocytoma tumours, subsequently discovering that GBM predominantly expresses Ca²⁺-permeable AMPA receptor subunits (GluA2 and GluA4), confirming that alterations in Ca²⁺ influx play a pivotal role in tumour growth. Additionally, transection of GBM cells with an edited version of GluA2 (GluA2R) inhibits cell migration and even induces apoptosis. In contrast, an unedited version of GluA2 (GluA2Q) enhances cellular malignant features [113]. The activation of the AMPA-Akt phosphorylation axis simultaneously promotes carcinoma proliferation by facilitating an excessive influx of Ca²⁺ [114]. The reduction of dsRNA editing levels at the GluA2Q/R site overall significantly enhances astrocytoma progression.

3.3.3. BC

The incidence of BC in women is characterized by a high mortality rate, making it the most malignant tumour among females and accounting for 7–10% of all types of malignant tumours in humans [115]. Among the subtypes of breast cancer, triple-negative breast carcinoma (TNBC) stands out as the most aggressive due to its lack of expression of estrogen receptor (ER), progesterone receptor, and protooncogene HER-2. The potential therapeutic target for TNBC is ADAR1, which plays a role in mediating the dsRNA A-to-I editing process and influencing its target level in BC [116–119]. The enzyme Dihydrofolate reductase (DHFR) plays a pivotal role in the metabolic pathway of folate and serves as a prime target for methotrexate. Elevated expression of DHFR confers resistance to methotrexate treatment in tumours. Suppression of ADAR1 leads to reduced RNA editing on DHFR, resulting in significant decreases in both DHFR mRNA and protein levels [119,120]. The results suggest that ADAR1 enhances the expression of DHFR. Moreover, BC tissues exhibit higher levels of ADAR1 expression and dsRNA A-to-I editing rate within the 3’-UTR regions of DHFR compared to adjacent normal tissues [119]. Recent studies have indicated that elevated expression of ADAR1 in TNBC may lead to poor prognosis when accompanied by increased dsRNA A-to-I editing rates [121,122]. The expression of ADAR1 is notably high in all subtypes of BC, thus the knockdown of ADAR1 can effectively impede cell growth and tumorigenesis [123]. The collective findings indicate that therapeutic inhibitors directed towards ADAR1 present a promising approach for mitigating TNBC.

3.3.4. PC

PC is a prevalent malignancy in the human digestive system, characterized by its high degree of malignancy. The expression of ADAR1 is upregulated during the onset and progression of PC, where it serves as a crucial biomarker for diagnosis and development. Pancreatic ductal adenocarcinoma (PDAC) represents a classical subtype of PC. CircNEIL3, a circular RNA molecule, functions as an oncogene in PDAC through the circNEIL3/miR-432-5p/ADAR1 axis, with ADAR1 being indirectly regulated by circNEIL3 as a downstream target of miR-432-5p. This regulatory loop involving circNEIL3/miR-432-5p/ADAR1 governs the proliferation and metastasis of PDAC via downstream GLI signaling or cell cycle and EMT pathway [124]. This implies that ADAR1 could serve as a therapeutic target for PC. Inhibition of ADAR1 to block the circNEIL3/miR-432-5p/ADAR1 pathway may have potential clinical implications in intervening with PC treatment.

3.3.5. Gastric cancer (GC)

The incidence and fatality of GC are globally significant, with it ranking third in terms of mortality rate [72]. The catalytic deaminase domains of ADAR1 and ADAR2 confer distinct roles as oncogenes and tumour suppressors, respectively [72]. The expression of ADAR1 is significantly upregulated in primary GC, whereas ADAR2 exhibits significant downregulation [125]. The decrease in editing activity is correlated with the functional impairment of the ADAR2 enzyme. In GC, deletion of the ADAR2 gene results in a reduction in ADAR2 expression [72]. The high expression of ADAR1 in GC cells, as demonstrated by in vitro tumorigenicity assays, suggests that its overexpression may be a specific characteristic contributing to the development of gastric carcinogenesis. Additionally, the PODXL gene encodes a protein that undergoes an amino acid substitution from His to Arg at codon 241. The specific regulation of this protein by ADAR2 weakens the oncogenic potential of unedited PODXL [72]. The inhibition of ADAR1 or activation of ADAR2 could be potential therapeutic strategies for GC treatment.

3.3.6. Esophageal squamous cell carcinoma (ESCC)

The predominant histological form of oesophageal cancer is ESCC, characterized by a heterogeneous tumour exhibiting a complex array of genetic and epigenetic alterations [126]. ADAR1 is upregulated in primary ESCC because of gene amplification, and patients with overexpression of ADAR1 exhibit a poor prognosis. In vitro and in vivo assays confirm the oncogenic role of ADAR1 during the initiation and progression of ESCC. Moreover, ESCC patients with elevated levels of ADAR1 experience shorter survival periods compared to other tumour phenotypes. Therefore, it can be inferred that the process of dsRNA A-to-I editing mediated by ADAR1 May further exacerbate the disease [126]. Conversely, the overexpression of ADAR2 in ESCC results in a decrease in cellular proliferation and an increase in apoptotic events. Moreover, xenografting nude mouse models exhibit significant reductions in tumour volumes and weights compared to their wild-type counterparts [127]. In essence, employing specific agents to facilitate ADAR2-mediated dsRNA A-to-I editing could serve as an efficacious therapeutic strategy for the treatment of ESCC.

3.3.7. Cervical carcinoma (CC)

CC is a prevalent malignancy among females, particularly impacting the health of women in developing countries. dsRNA-editing ADAR1 has been implicated in the occurrence and progression of CC. Firstly, CC exhibits high expression levels of ADAR1 [65]. The expression of CC gradually intensifies as the stages progress [65]. The findings suggest that increased expression of ADAR1 May contribute to the development of CC. Interestingly, ADAR1 expression is not only associated with processes related to metastasis, such as invasion and migration, but also closely linked to parametrial invasion, which serves as a prognostic factor [65]. The investigation of the underlying molecular mechanisms necessitates further studies.

3.3.8. Thyroid carcinoma (THCA)

THCA is the predominant type of thyroid malignancy, ranking ninth globally in terms of cancer incidence rates [128]. Numerous A-to-I editing sites have been identified in the untranslated dsRNA of THCA. The expression of ADAR1 and subsequent dsRNA A-to-I editing modulate the aggressiveness of THCA cells, thereby impacting their proliferation, invasion, migration, three-dimensional (3D) growth in vitro, as well as tumour growth in vivo [129]. The overediting of the tumour suppressor miR-200b in thyroid tumours is attributed to dsRNA A-to-I editing, which impairs its inhibitory effect on the epithelial-mesenchymal transition marker ZEB1. Restricting ADAR1 activity effectively curbs the proliferation, invasion, and migration capabilities of THCA [129]. The researchers have investigated that pharmacological inhibition targeting A-to-I editing in THCA cells leads to a reduction in aggressiveness in vitro [129]. The findings suggest that elevated levels of ADAR1 expression have a carcinogenic impact on THCA. In general, A-to-I editing sites could potentially serve as therapeutic targets for THCA. Targeted interventions directed at these specific sites would be significant in mitigating such tumours.

The expression of ADAR1 is observed to be upregulated across a range of cancers, including HCC, BC, PC, THCA, and GC. Conversely, there is a consistent downregulation of ADAR2 levels within these malignancies. Overall, depending on the tumour type and stage, ADARs exhibit diverse effects by influencing dsRNA editing processes that subsequently play distinct roles in carcinogenesis. Gaining insights into how ADARs contribute to the initiation and progression of human tumorigenesis could potentially lead to innovative approaches for developing anti-cancer therapies.

3.4. Metabolic diseases

3.4.1. Type 2 diabetes (T2DM)

The occurrence of metabolic diseases is attributed to disruptions in metabolic processes or excessive metabolic activities, which are indicative of systemic disorders affecting the human brain. T2DM is a metabolic disorder characterized by aberrant insulin secretion and impaired intracellular reuptake, often accompanied by hyperglycaemia and persistently elevated plasma glucose levels [130]. The glucose-stimulated insulin secretion by pancreatic β-cells plays a pivotal role in the pathogenesis of T2DM. Researchers have demonstrated that glucose stimulation upregulates the expression of ADAR2 in pancreatic β-cells via the c-Jun N-terminal kinase-1 pathway [131,132]. Furthermore, accumulating evidence suggests that the downregulation of ADAR2 significantly compromises insulin secretion, thereby highlighting its crucial role in maintaining optimal pancreatic β-cell function [133]. However, the precise targets of ADAR2 in the context of insulin secretion remain poorly elucidated, necessitating further investigation into its role in glucose-stimulated insulin secretion beyond pancreatic β-cells.

3.4.2. Chronic myeloid leukemia (CML)

The clonal malignant disease known as CML arises from aberrant differentiations of haematopoietic stem cells. The co-expression of the JAK-STAT pathway and BCR-ABL1 synergistically activates interferon signal transduction, resulting in elevated levels of ADAR1 in CML [134,135] (Figure 3). Additionally, there is an increased expression of inflammation-associated pathways and ADAR1p150 subtypes in it as well[135]. The presence of an increased number of dsRNA A-to-I editors is observed in advanced leukaemia [136]. A study on CML has demonstrated that ADAR1 editing results in a reduction of let-7 miRNA family members, which are known for their tumour-suppressive role [110,134,137–139]. By assessing the re-inoculation capacity in BALB/c mice, it was observed that ADAR1 exerts its influence on the overall let-7 levels exclusively through activation of leukaemic stem cell self-renewal [134]. Furthermore, it has been confirmed that let-7d, a member of the let-7 family, possesses multiple A-to-I editing sites within its encoded dsRNA sequence; one specific site significantly impacts its maturation efficiency [134]. The findings suggest that ADAR1 exerts its influence on the carcinogenesis phenotype by impeding the maturation processes of specific miRNAs.

Figure 3.

The diagram illustrates the immune exchange pathway mediated by ADAR1, a dsRNA A-to-I editing transformation modulating enzyme. In blast crisis CML, progenitors exhibit elevated levels of IFNγR1 and IL-3 Rα that can be activated by the JAK2 signalling pathway. Furthermore, the JAK2/STAT signalling pathway enhances ADAR1-mediated dsRNA editing. Amplification of BCR-ABL1 serves as a biomarker for blast crisis transformation simulating JAK2 activation, promoting self-renewal of progenitors through upregulation of LIN28B expression while impairing let-7 miRNA biogenesis. There exists a mechanistic relationship between oncogenic signalling pathways driven by inflammatory cytokines and malignant reprogramming of progenitors driven by dsRNA editing.

3.4.3. Dyspigmentation symmetrical hereditary (DSH)

The DSH is an uncommon autosomal dominant skin disorder characterized by hyperpigmentation, primarily affecting the anterior and posterior aspects of the limbs during infancy or early childhood [140]. Mutations in ADAR1 can impair the development of DSH. The initiation and progression of DSH are linked to heterozygous ADAR mutants. Gene mutations occurring in the deaminase domain of ADAR1 contribute to the pathogenesis of DSH in humans. More than 130 DSH-related mutants have been identified within the gene sequence of ADAR1, leading to disruption of type I interferon homoeostasis and subsequent manifestation of DSH [141]. Interestingly, it has been demonstrated that ADAR1 p150 plays a pivotal role in determining susceptibility to DSH, with haploinsufficiency serving as the genetic mechanism underlying this condition [142]. In zebrafish experiments, knockdown of ADAR1 resulted in aberrant migration of melanocytes and disrupted melanogenesis observed in skin lesions from patients with DSH [143]. Therefore, some researchers propose that the failure of RNA editing mediated by ADAR1 mutations hinders melanoblast differentiation, resulting in an uneven distribution of melanin and subsequent development of DSH skin lesions [144]. However, further research is necessary to gain a comprehensive understanding of the pathogenesis underlying DSH. Moreover, it should be noted that both AGS and DSH can coexist concurrently. Heterozygous mutations in ADAR1 have been reported to cause isolated instances of DSH; however, homozygous or compound mutations lead to a combined phenotype characterized by AGS features along with distinctive traits associated with DSH [145]. The investigation of ADAR1 mutations will contribute significantly to the elucidation of the underlying mechanisms involved in the pathogenesis of DSH.

Taken collectively, the dsRNA A-to-I editing facilitated by ADAR enzymes can exert a profound influence on the development and progression of metabolic disorders. For instance, during the initiation of CML, an observed upregulation of ADAR1 May potentially exacerbate the disease. Moreover, mutagenesis in ADAR1 has been discovered to induce symmetrical hereditary dyspigmentation. In contrast, expression of ADAR2 is associated with T2DM. To summarize, interference with the expression of distinct ADAR enzymes can modulate this process and subsequently modify pathogenesis. These investigations have raised the possibility that such process could serve as disease biomarkers and underscore ADAR family enzymes as potential targets for therapeutic intervention.

4. Discussion and prospects

Through literature mining, we have discovered that ADAR enzyme-mediated dsRNA A-to-I editing is implicated in the pathogenesis of various diseases. During tumorigenesis, ADAR1 exhibits high expression and functions as an oncogene, whereas ADAR2 acts as a tumour suppressor [34,146]. Additionally, we have observed that dsRNA A-to-I editing can interact with RNA modifications such as m⁶A and affect the expression of genes controlled by these modifications [23–25]. The impairment of disease progression has been reported in relation to various sites involved in this editing process, including the GluA2 Q/R site [59,60]. Although numerous functional dsRNA editing sites have been identified, the underlying mechanisms remain elusive. Modulating the expressions of ADAR family members to regulate the editing process could potentially serve as a gene therapy strategy for various diseases. However, effectively inhibiting ADAR1 expression or enhancing ADAR2 expression without adversely affecting other genes poses a challenge that necessitates further substantiation.

The expression of ADAR family enzymes is influenced by certain chemicals or small molecular inhibitors, which also intervene in the process of dsRNA A-to-I editing (Table 3). Consequently, these substances exert a regulatory effect on pathogenesis related to dsRNA editing or induced by it. For example, antidepressants have been found to enhance the editing activity in the encoded domain dsRNA sequences of 5-HT2C and GluA2 receptors [147]. The administration of compounds such as paroxetine and imipramine results in the upregulation of ADAR2 expression, thereby enhancing GluA2 editing ability at the Q/R site [92,148]. Reversely, cocaine decreases the expression of ADAR2 while diminishing its editing activity [149]. These pieces of evidence collectively suggest that natural herbs or chemical components may potentially play therapeutic roles in addressing neurological and neurodegenerative symptoms associated with dsRNA editing. Interestingly, Rebecsinib, a selective small-molecule inhibitor capable of eliminating ADAR1 splicing-mediated activations, can inhibit ADAR1p150 without causing significant adverse effects. This inhibition not only eradicates leukaemia stem cells but also preserves normal haematopoietic stem and progenitor cells [150]. Curaxin CBL0137, another inhibitor, directly triggers Z-DNA formation and effectively activates ZBP1 while inhibiting ADAR1. By suppressing endogenous Z-RNA and ZBP1-mediated necroptosis, ADAR1 serves as an emerging determinant of tumour immunogenicity that is concealed by its presence. Therefore, therapeutically inducing ZBP1-induced necroptosis provides a readily translatable pathway for rekindling immunoreactivity in ICB-resistant human tumorigenesis [42].

Table 3.

Intervention and activation of dsRNA A-to-I editing process.

Compound or Monomer Composition	ADAR	References
Cocaine	ADAR2	[149]
Antidepressants	ADAR2	[148]
Aflatoxin B1	ADAR	[151]
Benzo (a) Pyrene (bap-a)	ADAR2	[152] [153]
Hexavalent Chromium Ion (Potassium Chromate (VI))	ADAR2	[154]
Tetrachlorodibenzo Dioxin (TCDD)	ADAR2	[155]
Acrylamide	ADAR3	[156]
8-Azaadenosine	ADAR1	[129] [134]

In conclusion, this review offers a comprehensive overview of the dsRNA A-to-I editing process implicated in pathogenesis and emphasizes the significance of small molecular inhibitors, encompassing chemicals and active components that activate ADAR family enzymes. Furthermore, it explores the regulation of dsRNA A-to-I editing by active components. Given the implication of such editing sites in multiple diseases, it is imperative to investigate inhibitors that target specific editing sites to potentially modify pathogenesis and provide valuable insights for personalized remedies and precision medicine.

Funding Statement

The work was supported by the National Natural Sciences Foundation of China [No.82104494]; National Natural Sciences Foundation of China [No.U20A20405]; Shanghai Pujiang Program [No.23PJ1412300].

Highlights

• The ADAR family enzymes catalyzed the process of the dsRNA A-to-I editing, which is correlative to the pathogeneses such as tumorigenicity, autoimmune disorders, neurological and neurodegenerative symptoms as well as metabolic diseases.

• The ADARs family enzymes are targeted by certain small molecule inhibitors, which then carry out modulation activities involved in the process of dsRNA A-to-I editing or induced pathogeneses.

• The process of dsRNA A-to-I editing exerts an influence on RNA modifications, such as m⁶A, m⁵C and so on, thereby mutually impairing the pathogeneses.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Abbreviations

ADAR, adenosine deaminases ; A-to-I, Adenosine-to-Inosine; AGS, Aicardi-Goutières Syndrome; ALS, Amyotrophic lateral sclerosis; BLCAP, Bladder cancer-associated protein; BC, Breast carcinoma; BSN, Bilateral striatal necrosis; CML, chronic myeloid leukaemia; CC, Cervical carcinoma; CDC14B, cell division cycle 14B; DHFR, Dihydrofolate reductase; DSH, Dyspigmentation symmetrical hereditary; dsRNA, double-stranded RNA; ERE, endogenous retroviral elements; ESCC, esophageal squamous cell carcinoma; ER, estrogen receptor; eIF2α, eukaryotic initiation factor 2α; Gly, Glycine; GC, gastric cancer; GBM, Glioblastoma multiforme; GluA2, Glutamate receptor 2; HCC, Hepatocellular carcinoma; IFN, interferon; ICB, Immune Checkpoint Blockade; m⁶A,N6-adenosine methylation, m⁵C, cytosine hydroxylation; m¹A,N1-adenosine methylation; m⁷G,N7-methylguanosine methylation; PRR, pattern recognition receptor; PC, Pancreatic cancer; PDAC, Pancreatic ductal adenocarcinoma; RA, rheumatoid arthritis; SLE, Systemic lupus erythematosus; ssRNA, single-stranded RNA; Ser, Serine; T2DM, Type 2 diabetes; TNBC, triple-negative breast carcinoma; THCA, Thyroid carcinoma; Tetrachlorodibenzo Dioxin (TCDD); VSV, vesicular stomatitis virus; ZIKV, Zika virus; 5-HT, serotonin receptor; 5-HT2CR, The 5-HT2C receptor.

Author contributions

Wanqing Liu and Yufan Wu: Writing original draft preparation; Zizhao Yang, Tong Zhang, Xiaobo Sun, and Dean Guo: providing the editing and writing assistance and suggestions; Zizhao Yang and Dean Guo: approving the final version for publication. All the authors have made contributions to both the manuscript’s initiation and submission.

Data availability statement

As a review paper, this manuscript does not contain the source or experimental data, so this statement is to announce that our manuscript is irrelevant to any potential source or experimental data conflicts or issues.