Therapeutic Potential of the Protective Renin-Angiotensin System in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a significant global health challenge with high mortality rates, often diagnosed at advanced stages. Current treatments, including combination therapies with multikinase inhibitors and immune checkpoint inhibitors show suboptimal response rates, necessitating novel therapeutic strategies. The ren-in-angiotensin system (RAS), primarily known for its role in blood pressure regulation, also offers significant potential as a therapeutic target in HCC. While targeting the classical RAS with angiotensin II type 1 receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEi) can reduce HCC progression and angiogenesis in preclinical models, these drugs are often associated with severe off-target effects, in-cluding systemic hypotension and renal impairment. Conversely, the protective RAS, comprising angiotensin converting enzyme-2 (ACE2), angiotensin-(1-7) peptide and its putative receptor Mas, has been identified as a promising therapeutic target. Recent studies from our laboratory demonstrated that liver-specific, adeno-associated viral (AAV) vector-mediated ACE2 gene delivery markedly attenuated liver fibrosis, angio-genesis, and cell proliferation. By targeting the liver, AAV-mediated ACE2 therapy is expected to produce an optimal therapeutic response in HCC without having adverse off-target effects, thus establishing it as a safer and effective treatment modality. This review outlines current HCC treatment options while highlighting novel therapeutic approaches that target the ACE2-driven protective RAS.