Based on the above described hypothesis, inhibition of ACE2 pathway might be beneficial for COVID-19 patients. Indeed, the clinical picture as a whole is consistent with an ACE2 gain of function (possibly due to both circulating active forms of S1-sACE2 complexes and local forms of SARS-CoV-2-sACE2 complexes) rather than an ACE2 loss of function, as initially supposed. Therefore, inhibition of ACE2/Ang (1–7)/MasR axis or other ACE2 pathways to restore ACE/ACE2 balance might be needed, at least in the first phases of the disease when hypoxia is not yet induced. Different strategies could be pursued through ACE2 pathway inhibitors and/or MasR antagonists and/or renin inhibitors and/or metal chelators.