Novel insights into the regulatory role of N6-methyladenosine methylation modified autophagy in sepsis

Introduction

Sepsis is a potentially fatal organ failure brought on by an improperly controlled host response to infection [1], with a high morbidity and mortality rate worldwide. In 2017, the World Health Assembly listed sepsis as a global health priority [2]. Sepsis is one of the leading causes of death in the intensive care unit (ICU) [3]. According to statistics, sepsis accounts for 20% of annual deaths worldwide [4, 5]. Sepsis has a very complicated etiology that involves pathophysiological processes such as an excessive inflammatory response, pyroptosis, immunological dysfunction, mitochondrial damage, coagulation failure, oxidative stress, apoptosis, and autophagy, ultimately leading to organ dysfunction [6–10]. Over the past few decades, there have been efforts to come up with sepsis treatment strategies. In recent years, much progress has been achieved in the anti-infective, fluid resuscitation, hemodynamic sustain and organ function support therapy of sepsis using microbiology facilities and nanotechnology drug delivery platforms [11, 12]. However, the current clinical management of septic patients is still supportive rather than curative. It must be acknowledged that sepsis is a challenging issue for ICU physicians to overcome due to its multi-causal nature. Therefore, it is essential to study the molecular mechanisms underlying the biological processes involved in sepsis in order to optimize treatment options for the condition.

To date, there are more than 100 recognized modifications involved in regulating the bio-metabolic processes of RNA [13]. The most well studied RNA modification to date is N6-methyladenosine (m⁶A) methylation. Human messenger RNAs (mRNA), ribosomal RNAs (rRNA), and small nuclear RNAs (snRNA) all carry the m⁶A modification. m⁶A methylation is a reversible posttranscriptional modification of mRNA and regulates mRNA biogenesis and function [14]. Such modification regulates multiple steps of RNA processing including splicing, export, localization, decay and translation. More than 12,000 m⁶A loci were found in more than 7,000 human gene transcripts using antibody-mediated capture and massively parallel sequencing-based m⁶A-seq [15]. Studies have shown that m⁶A modification-related proteins are strongly associated with disease severity and prognosis [16, 17]. Especially, m⁶A methylation plays an essential role in inflammation by regulating three inflammatory signaling pathways including MAPK, JAK/STAT3, and PI3K [18]. Further data have demonstrated that METTL14-mediated m⁶A methylation negatively regulates inflammatory response in the context of sepsis [19]. It was discovered that insulin-like growth factor 2 mRNA binding proteins (IGFBPs), one of the m⁶A methylation binding proteins, influence the initial stages of septic shock [20]. Moreover, entire or RNA-specific therapeutic treatment of m⁶A methylation dynamics may be helpful to prevent and mitigate sepsis-induced disseminated intravascular coagulation [21]. In general, growing data suggests that m⁶A methylation is a mechanism that affects the onset and progression of sepsis. However, the regulatory function and underlying mechanisms of m⁶A in sepsis haven’t been thoroughly illuminated.

Under physiological environments, autophagic activity is often limited and serves as the cell’s guardian. However, when cells are exposed to outside stimuli such as pathogenic bacteria, hypoxia, and endotoxins, autophagic activity is significantly increased. Clearly, defects in the selective regulation of autophagy may lead to disease [22]. Autophagy is activated in the early stages of sepsis, followed by a phase of impaired autophagy [23]. Previous researches have shown that autophagy activation during sepsis is crucial for preventing subsequent lung, renal, and cardiac injury [24–26]. Existing research recognizes the critical role played by m⁶A methylation modification-related proteins in the biogenesis of autophagy [27, 28]. There is a growing awareness about the biological significance of the m⁶A modification on the transcription and translation of genes related to autophagy as well as the overall impact of conferring RNA specificity [29].

Clinically, m⁶A methylation-modified autophagy mechanisms play a crucial role in improving the prognosis of patients with sepsis [30]. There is no doubt that the connection between m⁶A methylation and autophagy will offer fresh perspectives on the management of sepsis. However, the effect of m⁶A-modified autophagy in the pathophysiology of sepsis remains largely unclear. Therefore, it is essential to clarify the potential mechanisms that revealing the exact biological processes and specific organ function-protective roles of m⁶A-modified autophagy in sepsis. The relative evidence that supports whether m⁶A methylation modified autophagy influences the pathophysiological mechanisms of sepsis is compiled in this review. The graphical abstract of this study is shown in Figure 1.

Figure 1. The overview of relationship between m⁶A methylation, autophagy, m⁶A-modified autophagy and sepsis.

How do m⁶A methylation modification-related proteins function during m⁶A methylation?

The METTL3-METTL14 compound is the ultimate important component in the writer proteins of m⁶A methylation. It is well established that the incidence of m⁶A methylation modification of various RNAs in mammals is inextricably linked to the activation of METTL3 and METTL14 [80]. In the process of m⁶A modification, METTL3 primarily functions as a catalytic core, while METTL14 provides a binding platform for RNA [81]. A recent study has shown that SUMOylation of METTL3 inhibits its m⁶A methyltransferase activity on RNAs [82]. The m⁶A methyltransferase’s core subunit, METTL14, works in stable heterodimer with METTL3 to catalyze m⁶A modification [83]. Subsequent research revealed that the methyltransferase activity of METTL3-METTL14 could only be elicited by the solution structure of the METTL3 zinc finger domain and not by the structural field of heterodimer between METTL14 and METTL3 [84]. Moreover, the METTL3-METTL14 complex is enlisted by WTAP, a regulatory subunit of the m⁶A methyltransferase complex, into nuclear patches that are enriched in pre-mRNA processing factors [85]. Prior works have also demonstrated that the mTORC1 modulates m⁶A methylation through regulating WTAP level to trigger the translational machinery for cell growth and proliferation [57, 86]. Contrary to the METTL3-METTL14 heterodimer, METTL16 is a single-component enzyme whose disordered loop is required to catalyze m⁶A methylation and whose N-terminal module is necessary for RNA binding [87]. Clearly, METTL16 in the cytoplasm and the nucleus serve different biological purposes. Only MAT2A mRNA and U6 snRNA were previously reported to directly deposit m⁶A from METTL16 [38, 88]. Reduced MAT2A mRNA degradation results from METTL16 localizing to hairpin 1 (hp1) on the 3’UTR of MAT2A mRNA and inducing MAT2A retained intron splicing [88]. In recent years, more RNAs with METTL16-mediated m⁶A methylation were reported in Supplementary Table 1 [43–79]. Additionally, wang, Fei et al. found that METTL16 facilitates mRNA 5 ‘cap-eIF4E recognition by sequestering eIF4E2 (translation initiation factor) [89]. Further studies suggest that this process of METTL16-mediated protein translation is independent of methyltransferase activity [89]. Therefore, in addition to catalyzing m⁶A methylation in the nucleus, METTL16 also participates in protein translation in the cytoplasm. The catalytic subunit m⁶A-METTL complex (MAC) and the regulatory subunit m⁶A-METTL-associated complex (MACOM) make up the m⁶A “writer”. The primary mechanism by which MACOM attaches to MAC is an interaction between WTAP and METTL3. Strikingly, WTAP and VIRMA comprise the basic structure of MACOM [90]. VIRMA recruits the METTL3/METTL14/WTAP, which are catalytic core components, to guide m⁶A methylation in 3’UTR and near stop codon of mRNA [91]. RBM15 plays a similar role to VIRMA in the methylation of m⁶A. RBM15 mediates m⁶A modification of targeted RNAs by targeting METTL3-METTL14 heterodimers to sites with or adjacent to m⁶A sites across the transcriptome [92]. ZCCHC4, a novel m⁶A methyltransferase that catalyzes m⁶A modification on rRNAs via binding to S-adenosyl-L-homocysteine, was recently reported [93]. ZCCHC4 is localized to the nucleolus, and ZCCHC4-mediated rRNA modification may also involve mRNA translation [94]. Further research established that ZCCHC4’s unique structural and enzymatic properties—namely, the formation of a complete RNA-binding surface by the association of the methyltransferase structural domain with the N-terminal GRF-type and C2H2 zinc finger structural domains and the C-terminal CCHC structural domain—are responsible for of its catalytic effect on rRNAs m⁶A modification [95].

m⁶A erasers predominantly catalyze demethylation of m⁶A-containing RNA. Two m⁶A demethylases have received a lot of attention to date: FTO and ALKBH5. FTO, one m⁶A eraser, primarily regulates the m⁶A modification in the nucleoplasm. FTO regulates pre-mRNA processing via its demethylation activity, which also influences mRNA stability close to the 7-methylguanosine cap, promotes cap-independent translation initiation at the 5’UTR, encourages exon jumping and alternative splicing at the pre-mRNA body, and modulates alternative poly(A) sites (APA) usage and 3’UTR length at the 3’UTR [96]. For instance, FTO can demethylate GAP-43 mRNA, and demethylation of GAP-43 mRNA may promote axonal elongation and regulate neural development [97]. ALKBH5, the other m⁶A eraser, localizes to nuclear speckles that are in charge of assembling mRNA processing factors. ALKBH5, a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX), has the potential to specifically bind single-stranded RNA attributed to a large loop (βIV–V) region that resembles the L1 loop of FTO [98]. ALKBH5’s demethylation activity has a momentous impact on gene expression, metabolism, and export of nuclear RNA (mainly mRNA), which regulates the biogenesis of m⁶A methylation on RNA [99]. In recent years, the crucial role of de-methylating of ALKBH5 in improving RNA stability has been particularly emphasized [100]. The demethylation of m⁶A modifications, exhibited by ALKBH5, improves the stability and expression levels of downstream RNAs that modulate heart regeneration and tumorigenicity [101, 102]. Does the m⁶A eraser’s demethylation activity work on methylated RNAs, though? A study offers an explanation: ALKBH5 and FTO keep their regulatory sites in an unmethylated stable state rather than reversing the methylated RNAs [103].

The variety of structural domains that m⁶A binding proteins possess allow for the division of these proteins into different families. Here, we’ll start out by introducing YTHDFs, which contain the YTH structural domain. YTH domain is known to directly bind the m⁶A base of methylated RNA [104]. YTHDF1 primarily recognizes the m6A methylation site of the downstream mRNA at the 3’UTR [66]. Mechanically, YTHDF1 recruits the transcripts of m⁶A-modified RNAs to facilitate their translation initiation [105], YTHDF2 induces the degradation of m⁶A-modified RNAs to decrease their stability [106], and YTHDF3 regulates the m⁶A methylation of downstream signal RNAs in synergy with YTHDF1 or YTHDF2 [107]. Contrary to these conventional beliefs, studies have proposed a novel unified model of m⁶A function, in which all m⁶A bits combine all three DF paralogs (YTHDF1, YTHDF2 and YTHDF3) in a fundamentally similar manner, influencing the degradation of mRNA through the interaction of these three key redundant DF proteins [108]. They did not, however, turn up any evidence that would support their hypothesis that these three DF proteins cooperating together have a role in promoting mRNA translation. Second, we’ll introduce the overview of YTHHDCs in the present paper, which share the same YTH structural domain. m⁶A methylation modification is a significant modality of regulation in mRNA splicing. The fate of the transcripts in terms of splicing dynamics and alternative splicing may be determined by early m⁶A sedimentation [109]. According to biochemical, structural, and transcriptome-wide PAR-CLIP (photoactivated ribonucleic acid enhanced cross-linking and immunoprecipitation) investigations, YTHDC1 is a nuclear RNA-binding protein that is responsible for recruiting mRNA splicing factors for pre-mRNA. The result from the current study has demonstrated that YTHDC1 promotes SRSF3 but antagonizes SRSF10 binding to RNAs at the m⁶A methylation site, further triggering the initiation of mRNA splicing [110]. It has been proposed that YTHDC2 may interact with translation and decay mechanisms in the context of particular binding to m⁶A in order to boost translation effectiveness and reduce the mRNA abundance of its targets [111]. Third, the identification of m⁶A by IGF2BPs depends on the K homology (KH) structural domain. Such m⁶A reading proteins selectively bind m⁶A-containing RNA using the KH structural domain and its flanking regions [104]. IGF2BPs have been reported to support the stability, storage and translation of their target mRNA transcripts by identifying their consensus GG-(m6A)-C sequences [78, 112]. The selectivity with which the remaining m⁶A reading proteins activate m⁶A causes them to be clustered together. Such m⁶A reading proteins bind m⁶A-containing transcripts through a m⁶A switch mechanism because the m⁶A modification weakens Watson-Crick base pairing of RNA and makes it easier for m⁶A reading proteins to recognize single-stranded RNA motifs; simultaneously, hnRNPA2B1 can also bind m6A-containing RNA with specificity by using the RRM structural domain and its flanking regions [104]. HNRNPG, a novel m⁶A methylation binding protein, binds purine-rich regions exposed by m⁶A modified RNA using its low-complexity region, regulating gene expression and selective splicing [42]. eIF3 binds directly to the 5’UTR m⁶A site of mRNA in the cytoplasm, which is sufficient to recruit the 43S complex and initiate translation in the absence of the cap-binding factor eIF4E [35, 113].

It is still controversial what function m⁶A-related proteins have in the pathogenic and physiological processes of the disease. For example, analysis reports of TCGA data indicate that high expression of METTL3 is associated with unfavorable prognosis in CRC patients [114]. Conversely, clinical research has demonstrated that METTL14 deletion is related to a poor prognosis in patients with CRC [52]. By modification of m⁶A, METTL3 can also assist in regulating the cardiac homeostasis and hypertrophy [115]. WTAP was also identified as an independent predictor of prognosis for patients with hepatocellular carcinoma [58]. According to one study, testicular Leydig cells experienced an increase in m⁶A methylation modification of RNA due to the inhibition of FTO, which led to apoptosis [116]. By examining the expression of m⁶A-related regulators and the probability of overall survival in HNSCC, Yu, Dan et al. discovered IGF2BP2 to be an independent prognostic factor in patients [77]. To sum up, various regulations of m⁶A methylation modification-related proteins play a critical role in the corresponding modified RNAs’ transcription by affecting their splicing, export, translation, and stability, which ultimately influences the development of these modified RNAs-mediated diseases. The diagrammatic sketch of these regulatory mechanisms is shown in Figure 2. It follows that m⁶A methylation is expected to develop as a therapeutic target for human diseases.

Figure 2. The sketch map of m⁶A methylation. Writers catalyze the m⁶A modification of RNA, erasers maintain the RNA in an unmethylated state, and the readers are ultimately responsible for determining the fate of the RNA (such as splicing, stability, degradation and translation).

However, as the field of study developed, we discovered that numerous m⁶A modification-related proteins interact to regulate the m⁶A methylation of targeted RNAs, rather than a single m⁶A modification-related protein, in the disease process. Many m⁶A methylation sites on SPRED2 mRNA have been found to be lost as a result of METTL3 deletion [117]. This impairs YTHDF1-mediated translation of the modified SPRED2 mRNA and increases NF-kB and STAT3 activation through the ERK pathway, which promotes tumor development and metastasis [117]. The level of SRY (sex determining region Y)-box 2 (SOX2) transcripts’ m⁶A methylation elevated as a result of METTL3. IGF2BP2 subsequently recognized methylated SOX2, maintaining its mRNA stability and expression. Ultimately, CRC development was triggered by high SOX2 expression [114]. However, when abundant in cellulose, METTL3’s role changes from catalyzing m⁶A methylation to promoting the initiation of mRNA translation. The production of dense polynucleotides, accelerated translation, and carcinogenic transformations all depend on METTL3-eIF3h interactions [118]. Moreover, another role m⁶A methylation frequently plays in disease development is targeted RNA degradation that is dependent on the METTL3-YTHDF2 interaction [73, 119]. METTL3 directs m⁶A modification of PKC-η, FAT4, and PDGFRA mRNAs to induce mRNA degradation via YTHDF2-dependent pathway, which promotes diabetes-related peripapillary cell dysfunction and stimulates retinal vascular complications [43]. As a result, METTL3 induces high levels of m⁶A modification in mRNA, and YTHDF2 identifies m⁶A sites in mRNA and promotes its degradation [120]. In the last resort, the synergistic effect of METTL3-YTHDF2 regulates the development of diseases via influencing disease-related genes expression. In a METTL3-FTO-dependent manner, m⁶A methylation plays the crucial role in the clinical and physiological processes of obesity cardiomyopathy, too [121]. ALKBH5 deletion leads to elevated m⁶A levels in downstream RNAs, and IGF2BP1 recognizes the exposed m⁶A sites and enhances their stability, thereby enhancing downstream RNA expression [122]. Similarly, ALKBH5-mediated m⁶A modification of its downstream targets is recognized by another m⁶A reader, YTHDF2, which is also responsible for degrading ALKBH5’s methylated downstream targets [123, 124]. Supplementary Table 1 [43–79] provides additional information on the essential role of writer/eraser-reader-dependent m⁶A methylation in the regulation of disease. In a word, m⁶A methylation is a dynamic and programmed process of RNAs modification. Even though each of the m⁶A modification-related proteins has a specific function, m⁶A modification of RNAs seems impossible to happen without the synergistic effect of these proteins. The level of RNAs’ m⁶A methylation in the nucleus is regulated by the m⁶A methyltransferases and demethylases, and the modified RNA enters the cytoplasm. Further affecting RNA splicing, degradation, stabilization, and translation are m⁶A binding proteins, which find and bind m⁶A residues on the transcript of the modified RNA. Therefore, this distinctive “writer/eraser-reader-dependent” paradigm for m⁶A methylation should be considered in the pathophysiological processes of disease, providing additional possibilities for therapeutic intervention.

Of course, the upstream signaling of m⁶A methylation-related proteins also influences their expression level, which in turn influences the level of downstream signaling that m⁶A regulates and, ultimately, the progression of the disease. For instance, Piwi-interacting RNA (piRNA)-14633 interacts with the 3’UTR of METTL14 to enhance the stability of METTL14 mRNA and encouraged the methylase activity of METTL14, promoting the m⁶A methylation levels of the downstream target (CYP1B1), and subsequently promoting the expression of CYP1B1, which in turn contributed to the oncogenesis of cervical carcinoma [53]. Additionally, by interacting with METTL3 and inhibiting its RNA methylation activity, cardiac-hypertrophy-associated piRNA (CHAPIR) prevents the m⁶A modification of PARP10 mRNA. This causes a blockage of the YTHDF2-mediated degradation of the PARP10 mRNA transcripts and an increase in PARP10 expression, which leads to cardiac hypertrophy [119].

The indirect regulatory role of m⁶A methylation in autophagy

The m⁶A modification can also indirectly regulate maturity of autophagy by affecting the activity of the autophagy-related pathways. Additionally, there are both negative and positive correlations between m⁶A alterations and pathways involved in autophagy. We preferentially focus on expanding the conversation around negative regulation. Autophagy is positively regulated by the AMPK pathway in the progression of sepsis-induced cardiomyopathy [155]. Previous research has shown that m⁶A methylation inhibits autophagy by increasing the translation of protein phosphatase 1A (PPM1A), an AMPK negatively regulated factor, which is mediated by YTHDF1, while decreasing the stability and expression of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), an AMPK actively regulated factor, which is mediated by YTHDF2 [156]. They also found that a decrease in METTL3 and METTL14 and an increase in ALKBH5 in the process [156]. In the same way, our research goes further and focuses on the LKB1, an upstream kinase of AMPK. WTAP-mediated m6A methylation impaired the stability and expression of LKB1 mRNA, which prevents the AMPK pathway from being activated and inhibits autophagic flux [157]. Additionally, SIRT1 pathway activates autophagy by deacetylating a variety of ATGs. Mechanically, METTL14-dependent m⁶A modification mediates the degradation of SIRT1 mRNA, which provide a potential possibility for curbing autophagy [158]. On the other hand, the synergy of tumor protein p53 inducible nuclear protein 2 (TP53INP2) with LC3 and ATG7 is also critical for autophagy activation. FTO induces the decreased m⁶A modification of TP53INP2 transcript as well as high expression of TP53INP2, which ultimately promotes autophagy [159]. In response to extracellular stress, the FOXO3 pathway maintains cellular homeostasis by acting on high levels of intracellular ROS to mediate autophagy [160]. METTL3-induced m⁶A methylation decreases autophagic flux through enhancing FOXO3 RNA stability and expression in an YTHDF1-dependent manner [161]. Similar to the above, Rubicon is a cellular autophagy negative regulator gene that binds to Beclin1 to inhibit the autophagic pathway; METTL3-YTHDF1-dependent m⁶A methylation also decreases autophagic flux by enhancing the stability and translation of Rubicon mRNA [162]. Initial observations suggest that PI3K/AKT/mTOR signaling pathway plays an important role in the anti-autophagy effect [163]. IGF2BP3 promotes translation machinery associated 7 homolog (TMA7) mRNA stability and translation through recognition of the m⁶A site on the TMA7 3’-UTR, which in turn activates the PI3K/AKT/mTOR pathway and ultimately inhibits autophagy [164]. Conversely, activating transcription factor 4 (ATF4) negatively regulates the mTOR signaling pathway. High expression of FTO maintained ATF4 mRNA at unmethylated steady-state levels, and YTHDF2 was unable to induce degradation of ATF4 in the cytoplasm because it failed to recognize m⁶A residues on ATF4 mRNA transcripts, thus increasing ATF4 expression levels and activating the mTOR-suppressed autophagic pathway [165]. Overall, the m⁶A modification negatively regulates autophagic activity mainly by mediating the expression of upstream signaling pathways of autophagy regulators.

Then, we develop the discussion of positive regulation. ALKBH5-mediated reduction of m⁶A methylation indirectly inhibits the development of autophagy by regulating the expression of GSK3β/mTOR signaling pathway [166]. Earlier, study has observed that miR-199a impairs autophagy in thick heart muscle cells in a cell-autonomous way through targeted GSK3β/mTOR signal pathway [167]. More precisely, autophagy is negatively regulated by the GSK3β/mTOR signal pathway [168]. USP13 is known to be an essential deubiquitinase that stabilizes ATG5 by deubiquitination. Mechanically, USP13’s m⁶A modification is catalyzed by METTL3, and IGF2BP2 promotes USP13 mRNA translation by identifying m⁶A residues on USP13 transcripts, ultimately triggering autophagy [169]. Decapping Protein 2 (DCP2) is degraded as a result of METTL3’s induction of m⁶A methylation, which facilitates mitophagy via the Pink1-Parkin pathway [170].

To sum up, a sizable and intricate regulatory network of signaling pathways exists upstream of the autophagy regulators, and m⁶A modification in any member of this regulatory network will govern the bioprocess of autophagy by affecting the expression of its downstream signals. As shown in Figure 3, the aforementioned empirical findings in the present study provide a new understanding of m⁶A methylation regulates autophagy. First, we summarize the regulation of m⁶A methylation in the biological metabolism of autophagy as a “writer/eraser-reader-dependent” model, where the “writer” is mainly responsible for catalyzing the m⁶A modification of RNA, while the “eraser” maintains the RNA in an unmethylated state, and the “reader” is ultimately responsible for determining the fate of the RNA. Second, two approaches exist for m⁶A methylation to control autophagic activity: directly by altering the autophagic regulators themselves, or indirectly by altering the upstream signaling pathways that mediate the autophagic regulators’ expression. Then, m⁶A modification up-regulates autophagic activity by inhibiting the degradation of autophagy-negative factors or encouraging the expression of factors that promote autophagy. Conversely, it down-regulates autophagic activity. Last but not least, m⁶A modifications have an impact on autophagy regulators and autophagic activity by mediating the expression and degradation of the regulators’ upstream signaling pathways.

Figure 3. A summary of molecular mechanisms of m⁶A-modified autophagy on sepsis. Red arrows represent the role of m⁶A methylation in maintaining the stability of autophagy regulators and their upstream signaling pathways; Blue arrows represent the degradation of autophagy regulators and their upstream signaling pathways by m⁶A methylation.

Abbreviations

m⁶A: N6-methyladenosine; ICU: intensive care unit; mRNA: messenger RNAs; rRNA: ribosomal RNAs; snRNA: small nuclear RNAs; IGFBPs: insulin-like growth factor 2 mRNA binding proteins; MAT2A: methionine adenosyltransferase 2A; METTL16: methyltransferase-like 16; SAM: S-adenosylmethionine; METTL3: methyltransferase-like 3; METTL14: methyltransferase-like 14; METTL5: methyltransferase-like 5; WTAP: Wilms tumor 1-associated protein; VIRMA: Vir-like m⁶A methyltransferase associated; RBM15: RNA binding motif protein 15; ZCCHC4: zinc-finger CCHC domain-containing protein 4; FTO: fat mass and obesity-related proteins; ALKBH5: alkB homolog 5; YTHDF 1-3: YTH structural domain family 1-3; YTHDC 1-2: YTH structural domain containing family 1-2; eIF3: eukaryotic translation initiation factor 3 subunit A; IGF2BP1/2/3: insulin-like growth factor 2 mRNA binding protein 1/2/3; HNRNPA2/B1: heterogeneous nuclear ribonucleoprotein A2/B1; MAC: m⁶A-METTL complex; MACOM: m⁶A-METTL-associated complex; NAOX: nucleic acid oxygenase; SOX2: SRY (sex determining region Y)-box 2; piRNA: Piwi-interacting RNA; CHAPIR: cardiac-hypertrophy-associated piRNA; HR: hazard ratio; LPS: lipopolysaccharide; ARDS: acute respiratory distress syndrome; TFEB: Transcription factor EB; PPM1A: protein phosphatase 1A; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2; TP53INP2: tumor protein p53 inducible nuclear protein 2; TMA7: translation machinery associated 7 homolog; ATF4: activating transcription factor 4.

Author Contributions

LS Y and JF Z performed study concept and design; CF B performed drawing of mechanism diagrams and writing, review and revision of the paper; JL and XD H provided acquisition, analysis and interpretation of materials. All authors have reviewed the final version of the manuscript and approved it for publication.

Acknowledgments

The authors thank Department of Emergency Medical, General Hospital of Ningxia Medical University for supporting this work.

Conflicts of Interest

All authors declare that there are no conflicts of interest.

Funding

This review is supported by research grants from the National Natural Science Foundation of China (82205116) and the Natural Science Fund of Ningxia (2022AAC03593).

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