Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas

Abstract

Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid β-oxidation regulated by PPARα, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45+ immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid β-oxidation and glycolysis. Increased lipid metabolism via PPARα may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties.