Human and mouse adrenal glands are characterized by species-specific steroidogenic states and tissue turnover

Abstract The adult adrenal cortex undergoes constant renewal, yet underlying human-specific mechanisms remain poorly understood. Here we generated single-cell and spatial transcriptomic atlases of adult human and mouse adrenal glands, leveraging single-cell-resolution spatial data and a rare clonal mosaic case for lineage inference. In humans, we identified age-associated zona glomerulosa (ZG) cell states with direct cortisol synthesis capacity and sex-specific differences in inferred cholesterol balance. Cross-species comparison revealed conserved aldosterone-producing ZG but notable divergence in zona fasciculata markers, absence of zona reticularis homologs in mice and differential SHH–WNT4 signaling in proliferating cells. We uncovered human WT1 − capsule-to-ZG transition and vascular smooth muscle cell-to-steroidogenic transitions supported by mosaic lineage evidence. We revealed dispersed proliferating cortical SF1 + EZH2 + cells throughout the human cortex in contrast with ZG restriction in mice. Taken together, our data expand the centripetal renewal model and establish a comparative framework for human adrenocortical biology.