Progress in research on RAAS inhibitors regulating inflammatory responses and oxidative stress: from molecular mechanisms to clinical evidence

The renin-angiotensin-aldosterone system (RAAS) inhibitors serve as cornerstone pharmacotherapies for chronic conditions including hypertension, heart failure, and chronic kidney disease. Accumulating evidence over recent years has demonstrated that their target organ-protective effects cannot be fully attributed to blood pressure-lowering actions alone; instead, the modulation of inflammatory responses and oxidative stress emerges as a core mechanism underpinning their extra-antihypertensive benefits. However, systematic comparisons of such effects across distinct classes of RAAS inhibitors and integration of the latest evidence remain lacking. This review focuses on the molecular regulatory network of the dual RAAS axes, systematically dissecting the specific molecular mechanisms by which the canonical ACE-AngII-AT1R axis mediates tissue injury-via activation of the NLRP3 inflammasome, NADPH oxidase, and NF-κB signaling pathways-while the protective ACE2-Ang(1-7)-MasR axis exerts anti-inflammatory and antioxidant effects. A cross-class comparison is conducted to evaluate the divergent effects of five clinically prevalent RAAS inhibitor classes (ACE inhibitors [ACEI], angiotensin receptor blockers [ARB], direct renin inhibitors [DRI], angiotensin receptor-neprilysin inhibitors [ARNI], and mineralocorticoid receptor antagonists [MRA]) on the regulation of inflammation and oxidative stress. By synthesizing the latest evidence from basic science and clinical studies over the past decade, we summarize the distinct organ-protective profiles of these agents across various target organs affected by cardiovascular disease, chronic kidney disease, pulmonary disorders, neurological conditions, rheumatoid arthritis, and osteoporosis. Finally, addressing the limitations and inconsistencies within existing literature, this article proposes future research directions, strategies for optimizing combination therapies, and refined clinical trial designs to enhance the clinical application of RAAS inhibitors and facilitate the development of novel organ-protection paradigms.