Exploring m6A‐RNA methylation as a potential therapeutic strategy for acute lung injury and acute respiratory distress syndrome

Abstract

N6‐methyladenosine (m6A) is the most common methylation modification in mammalian messenger RNA (mRNA) and noncoding RNAs. m6A modification plays a role in the regulation of gene expression and deregulation of m6A methylation has been implicated in many human diseases. Recent publications suggest that exploitation of this methylation process may possess utility against acute lung injury (ALI). ALI and its more severe form, acute respiratory distress syndrome (ARDS) are acute, inflammatory clinical syndromes characterized by poor oxygenation and diffuse pulmonary infiltrates. This syndrome is associated with microvascular endothelial dysfunction, subsequent pulmonary hypertension and may ultimately lead to mortality without rigorous and acute clinical intervention. Over the years, many attempts have been made to detect novel therapeutic avenues for research without much success. The urgency for the discovery of novel therapeutic agents has become more pronounced recently given the current pandemic infection of coronavirus disease 2019 (COVID‐2019), still ongoing at the time that this review is being written. We review the current landscape of literature regarding ALI and ARDS etiology, pathophysiology, and therapeutics and present a potential role of m6A methylation. Additionally, we will establish the axiomatic principles of m6A methylation to provide a framework. In conclusion, METTL3, or methyltransferase‐like 3, the selective RNA methyltransferase for m6A, is a hub of proinflammatory gene expression regulation in ALI, and using a modern drug discovery strategy will identify new and effective ALI drug candidates targeting METTTL3.

RNA modifications in pulmonary diseases

“…In addition, PM2.5‐induced upregulation of YTHDF1 additionally boosts the translation efficiency of IL‐24 mRNA. Therefore, m 6 A regulators mediate inflammatory damage through METTL3/YTHDF1 168 . In the induction of microvascular injury by PM2.5, METTL16 m 6 A modifications are additionally implicated, thereby fostering the progression of COPD 169 .…”

Tamping Down the Fire: Taming Pyroptosis through RNA Methylation in Acute Lung Injury

“…N 6 -methyladenosine (m 6 A) is the most prevalent internal mRNA modification and plays multiple roles in regulating mRNA metabolism and gene expression, including mRNA splicing, nuclear export, translation, and stability ( 4 , 5 ). Dysregulated N 6 methylation has been implicated in multiple human diseases, including ARDS ( 6 ). Adenosine methylation occurs in the nucleus through the action of a METTL3 (Methyltransferase like 3)-containing methyltransferase complex.…”