FOS and JUN regulate oxidative stress and steroidogenesis in human aldosterone-producing adenomas

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA). While oxidative stress and steroidogenesis are intricately linked in adrenal disorders, their interplay and mechanistic basis in APA pathogenesis remain to be fully elucidated. Here, by integrating RNA sequencing of oxidative stress-exposed human adrenocortical cells with spatially-resolved transcriptomic profiling of human adrenal sections, we propose a previously unrecognized role for the activator protein-1 (AP-1) transcription factors FOS and JUN as key mediators linking oxidative stress to steroidogenesis in PA. Their expression and activation are spatially restricted, coinciding with regions of elevated oxidative stress. Phosphorylated FOS and JUN were exclusively detected in the adrenal cortex adjacent to functional adenomas (APAs and cortisol-producing adenomas), with negligible levels in cortex adjacent to non-functional adenomas and in normal adrenal cortex. In vitro, oxidative stress induced the upregulation and activation of FOS and JUN. Conversely, co-overexpression of FOS and JUN suppressed key steroidogenic genes (StAR, CYP11B1, CYP11B2), reduced aldosterone and cortisol secretion, and increased reactive oxygen species accumulation. Together, this work demonstrates that FOS and JUN may function in coordinating the redox-steroidogenesis axis, linking molecular changes in the adjacent cortex to tumor function and microenvironmental remodeling.