This article reviews the correlation between ACE2 and severe risk factors for COVID-19 and the possible mechanisms. Angiotensin-converting enzyme 2 (ACE2) is a crucial component of the renin-angiotensin system (RAS). The classical RAS ACE-Ang II-AT1R regulatory axis and the ACE2-Ang1-7-MasR counter-regulatory axis play an essential role in maintaining homeostasis in humans. ACE2 is widely distributed in the heart, kidneys, lungs, and testes. ACE2 antagonizes the activation of the classical RAS system and protects against organ damage, protecting against hypertension, diabetes, and cardiovascular disease. Similar to SARS-CoV, SARS-CoV-2 also uses the ACE2 receptor to invade human alveolar epithelial cells. ARDS is a clinical high-mortality disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of patients with COVID-19 is related to factors such as sex (male), age (higher than 60 years), underlying diseases (hypertension, diabetes, and cardiovascular disease), secondary ARDS, and other relevant factors. Because of these protective effects of ACE2 on chronic underlying diseases and ARDS, the development of spike protein-based vaccine and drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID-19 in the future. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.