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

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 (m⁶A) 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 m⁶A 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 m⁶A 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, m⁶A 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 m⁶A regulators in alveolar cells, myeloid cells, and fibroblasts may induce pulmonary injury in patients. The development of m⁶A-regulator inhibitors could be as one potential antifibrotic drugs for COVID-19.