Unlocking the potential of the ACE2/Ang-(1-7)/Mas Axis in liver diseases: From molecular mechanisms to translational applications.

Over the past two decades, the identification of new functions within the renin-angiotensin system (RAS) has extended beyond its traditional roles, with the emergence of the angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas axis being particularly significant. This axis is hypothesized to balance or modulate the effects of the traditional ACE/Ang II/AT1 axis in various physiological and pathological contexts. ACE2, a membrane-bound carboxypeptidase and an ancient homologue of ACE converts Angiotensin II (Ang II) into Angiotensin 1-7 (Ang-(1-7)). The Mas receptor is a G-protein-coupled receptor that specifically binds Ang-(1-7). Recent research has increasingly focused on the local expression of RAS in different tissues. Ang-(1-7) produces a variety of biological effects by binding to the Mas receptor, including anti-inflammatory, antioxidant, anti-apoptotic and anti-fibrotic actions, thereby influencing a range of mechanisms in the heart, kidneys, brain and other tissues. Preclinical animal model studies indicate that manipulating the protective RAS can significantly alter the progression of multiple liver diseases. Hepatic overexpression of ACE2 or administration of Ang-(1-7) and its analogues has been shown to be therapeutically effective against drug-induced liver injury, metabolic-associated fatty liver disease, liver fibrosis and hepatocellular carcinoma progression. These effects are achieved through various pathways, including the regulation of lipid metabolism, inhibition of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) production, as well as suppression of aerobic glycolysis. In current clinical trials, while recombinant human ACE2 (Rh-ACE2) has demonstrated safety and good tolerance in most studies, research on the relevance of activating the ACE2/Ang-(1-7) axis in the mechanisms and evolution of human diseases remains in its early stages. Therefore, further elucidation of the complex interactions between the classical and counter-regulatory RAS axes in clinical settings is crucial. This review will summarize the roles of selective activation of the ACE2/Ang-(1-7)/Mas axis, with a focus on its mechanisms in the treatment of liver diseases. Additionally, we will discuss the safety concerns regarding selective activation of the ACE2/Ang-(1-7)/Mas axis in clinical applications and the challenges of tissue-specific activation of this axis, providing effective therapeutic strategies for targeted activation of the hepatic ACE2/Ang-(1-7)/Mas axis in clinical practice.