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Conventional therapies, renin\u2013angiotensin\u2013aldosterone system (RAAS) inhibitors, and mineralocorticoid receptor antagonists attenuate downstream receptor signaling but do not suppress aldosterone biosynthesis, allowing residual hormonal activity that perpetuates tissue damage. The long\u2010term efficacy, endocrine selectivity, and clinical significance of directly inhibiting aldosterone synthesis, however, remain only partly defined, particularly with respect to sustained aldosterone suppression, preservation of cortisol production, and applicability across diverse cardiorenal disorders. This review provides a comprehensive and mechanistically focused synthesis of preclinical and clinical evidence on aldosterone synthase inhibitors (ASIs), examining their pharmacologic specificity, hormonal effects, and emerging therapeutic potential in primary aldosteronism (PA), resistant hypertension, and CKD. Next\u2010generation ASIs\u2014including baxdrostat, lorundrostat, dexfadrostat phosphate, and vicadrostat\u2014demonstrate &gt;100\u2010fold selectivity for CYP11B2 over CYP11B1, enabling potent and reversible aldosterone suppression while maintaining cortisol biosynthesis. Across early\u2010phase trials, these agents consistently reduce aldosterone concentrations, lower systolic and diastolic blood pressure, decrease albuminuria, and normalize potassium balance in PA, with favorable safety and minimal hypothalamic\u2013pituitary\u2013adrenal axis disturbance. Collectively, these findings position ASIs as a selective and mechanistically coherent therapeutic strategy that addresses residual aldosterone activity beyond conventional RAAS blockade. Although current evidence relies largely on surrogate endpoints, ongoing phase III outcome trials will determine whether ASIs can translate mechanistic promise into durable cardiovascular and renal protection, potentially redefining the therapeutic landscape of aldosterone\u2010mediated diseases.<\/jats:p>","DOI":"10.1111\/joim.70061","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:01:18Z","timestamp":1767679278000},"page":"425-443","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Aldosterone synthase inhibitors across the translational spectrum: Mechanistic foundations and emerging clinical applications"],"prefix":"10.1111","volume":"299","author":[{"given":"Matteo","family":"Merlo","sequence":"first","affiliation":[{"name":"Department of Medicine Unit of Internal Medicine B University of Verona School of Medicine Azienda Ospedaliera Universitaria Integrata Verona Policlinico \u201cG.B. 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