Epigenetic regulation by nitrosative stress as a potential mechanism of long COVID

After recovering from COVID-19, some patients develop post-acute sequelae known as long COVID; however, the underlying mechanisms remain poorly understood. SARS-CoV-2 infection drives the aberrant expression of inducible nitric oxide synthase, triggering excessive nitric oxide generation. Here, we showed the direct evidence of the pathophysiological relevance of nitrosative stress in long COVID with measuring total S-nitrosylated protein levels in the plasma of long COVID patients. We found that the non-canonical activation of hypoxia-inducible factor (HIF) via DNA hypomethylation through S-nitrosylation of DNA methyltransferase, resulting in epigenetic gene upregulation of target genes in normal human cells. Remarkably, the expression levels of genes showed the sensitivity against specific inhibitor of S-nitrosylation of DNMT3B were significantly elevated in long COVID patients. Collectively, these findings suggest that nitrosative stress, particularly epigenetic gene regulation, is a potential mechanism of long COVID.