Cell‐type‐specific mRNA m6A landscape and regulatory mechanisms underlying pulmonary injury in COVID‐19

Abstract Coronavirus disease 2019 (COVID‐19) pandemic has caused millions of deaths. The risk of COVID‐19 spreading still exists after the deconfinement act, Omicron became the dominant variant. Although N6‐methyladenosine (m 6 A) regulators has been reported to affect the pathogenicity of COVID‐19, their mechanism in the progression of lung injury in COVID‐19 patients remain elusive. Here we show the landscape and specific mechanisms of m 6 A regulators in lung tissues through single‐nucleus RNA sequencing (snRNA‐Seq) data sets of 116,252 cells, and the external validation was performed using data from another snRNA‐Seq data. The m 6 A reader IGF2BP2 was specifically upregulated in alveolar type I (AT1) cells, resulting in impaired lung regeneration. ALKBH5 expression upregulation in macrophages, impairing immune responses. Moreover, WTAP markedly upregulated in fibroblasts, leading to pulmonary fibrosis. In addition, m 6 A regulators dysregulation induced aberrant cell–cell communication in pulmonary tissue and mediated ligand–receptor interactions across diverse cell types in lung tissues by activating the TGF‐β signaling pathway. Overall, these results indicated that the upregulation of m 6 A regulators in alveolar cells, myeloid cells, and fibroblasts may induce pulmonary injury in patients. The development of m 6 A‐regulator inhibitors could be as one potential antifibrotic drugs for COVID‐19.