ACE2, a therapeutic target of COVID-19, needs to be treated with caution.

Angiotensin-converting enzyme 2 (ACE2) has garnered significant attention for its crucial role in infection by both SARS-CoV and SARS-CoV-2. Consequently, it has emerged as a potential therapeutic target for treatment of COVID-19. It is therefore important to understand the mechanisms and modes of action of current and future treatments involving ACE2. Three important strategies have been explored in previous studies: (1) interruption of the interaction between ACE2 and the coronavirus spike protein using compounds or monoclonal antibodies, (2) capturing the extracellular virus by employing soluble ACE2 as a decoy, and (3) reducing the expression or inhibiting the activity of ACE2 through genetic approaches or drug intervention. However, the third strategy of inhibiting ACE2 activity as a means of treating COVID-19 is potentially risky, and the wisdom of pursuing this approach is subject to debate. Here, the advisability of using anti-ACE2 treatment in the context of SARS-CoV and SARS-CoV-2 infections is challenged by reviewing the physiological function of ACE2 and the mechanism of viral entry, emphasizing the pathological impairment of ACE2 that occurs during SARS-CoV and SARS-CoV-2 infection and arguing that the potential hazards associated with ACE2 impairment should be given more attention. Because of the important concerns regarding the potential side effects of ACE2 inhibition, researchers are strongly urged to approach this issue with caution.