Decoding Adrenal Cellular Heterogeneity in Primary Aldosteronism by Single-Cell Analysis

Abstract Primary aldosteronism (PA), characterised by autonomous aldosterone excess, accounts for a substantial proportion of patients with hypertension, particularly those with resistant disease. Current clinical management is largely guided by a binary classification into unilateral and bilateral PA; however, accumulating clinical, pathological, and molecular evidence indicates that this framework inadequately captures the underlying biological heterogeneity. Variable surgical outcomes, biochemical recurrence following adrenalectomy, and refined aldosterone synthase (CYP11B2)-based histopathological classifications highlight PA as a disease spectrum driven by disrupted adrenal zonation, cellular plasticity, and diverse aldosterone-driving somatic mutations. Despite major advances in defining the molecular basis of PA over the past decade, most insights have been derived from bulk genetic analyses of surgically excised tissue, limiting resolution of cellular heterogeneity and disease evolution. In this review, we integrate current understanding of PA pathophysiology with recent advances in single-cell and spatial technologies that have transformed adrenal research. We outline key methodological approaches enabling high-resolution interrogation of adrenal development, tumour heterogeneity, and the adrenal microenvironment. Finally, we discuss the translational implications of single-cell insights for PA, including improved patient stratification, identification of pre-operative biomarkers, and the development of mechanism-based, genotype-informed therapies beyond conventional mineralocorticoid receptor antagonism. Collectively, these advances support a paradigm shift from lateralisation-based management toward precision approaches targeting the cellular and molecular drivers of aldosterone excess.