Single-cell transcriptomic analysis reveals metabolic reprogramming and tumor microenvironment remodeling in aldosterone-producing adenoma

Abstract

Aldosterone-producing adenoma (APA) is a significant cause of primary aldosteronism, however, its cellular heterogeneity remains unclear. We performed single-cell RNA sequencing on adrenal tissues from three APA patients and three controls. We identified CAPS⁺ zona glomerulosa (ZG)-like cells in APA with upregulated lipogenesis, oxidative phosphorylation, and mTOR signaling, indicating metabolic reprogramming. Pseudotime analysis revealed disrupted differentiation and aberrant CYP11B1, CYP11B2, and SULT2A1 expression. Oncogenic Myc, Wnt, and G2/M pathways were activated in ZR-like clusters. APA showed immune infiltration (B cells, CD8⁺ T cells, M1 macrophages), angiogenic activation (VWF⁺ endothelial cells), and fibroblast-driven stromal remodeling via Hedgehog signaling. Our study provides a comprehensive single-cell atlas of APA, uncovering key tumorigenic mechanisms and identifying potential biomarkers (e.g., CAPS, VWF, UPK3B) and therapeutic targets, including mTOR and Hedgehog/Wnt pathways. These findings advance the genomic understanding of adrenal tumors and support precision medicine development.

Keywords: Aldosterone-producing adenoma; Cell differentiation; Metabolic reprogramming; Single-cell RNA-seq; Tumor microenvironment.