Taken together, these findings strengthen the hypothesis that SARS-CoV-2-induced HEPHL1 dysregulation might promote several detrimental effects in SARS-CoV-2-related lung damage, which not only explains the main clinical manifestations of severe COVID-19 patients, including hypoxemia and dyspnea, but also contributes as the possible underlying mechanism of extracellular microenvironment dysregulation and iron accumulation in the lung tissue, which triggers pulmonary fibrosis and lung function decline following SARS-CoV-2 infection. The gene discussed is HEPHL1; the disease is COVID-19.