Endocrine Abstracts

Background: The role of ferroptosis – a regulated form of cell death – in the pathophysiology of aldosterone-producing adenomas (APA) is unclear.

Objective: To identify mechanisms of ferroptosis in human adrenal cells and translate these findings to APA pathophysiology.

Methods: Cell death detection, lipid ROS generation and mRNA sequencing were performed on HAC15 cells treated with the specific ferroptosis inducer RSL3 (1, 2 and 4 mM), in the presence and absence of the ferroptosis antagonist Liproxstatin-1. Volcano plots and heat maps were used to visualize RNAseq data from RSL3-treated HAC15 cells. Transcriptomics data of APAs versus adjacent cortex were mined from a publicly available transcriptome dataset (GSE60042). Spatial gene expression profiles of selected genes of interest were generated in 8 cryosections of APAs and paired adjacent cortex.

Results: RSL3 induced a liproxstatin-1 sensitive, dose-dependent effect on HAC15 cell death and lipid ROS generation. Genes which were differentially expressed in both RSL3-treated HAC15 and in APAs were identified and considered as genes of interest. RSL3 induced dose-dependent increases in HMOX1, UNKL and TRIB1 gene expression in HAC15 cells. The spatial transcriptomics dataset showed decreased HMOX1, UNKL and TRIB1 expression in APA tumor tissue relative to the adjacent cortex. Therefore, we identified genes with a putative function in the promotion of ferroptosis in human adrenal cells which were downregulated in APA tumors.

Conclusion: Suppression of cell death by ferroptosis may play a key role in APA pathophysiology.