Proteomic profiling reveals novel insights into hypercortisolism adrenal adenomas

Adrenal cortisol-producing adenomas (CPAs) represent the most common endocrine disorder among adrenal incidentalomas and are classified as either subclinical Cushing's syndrome (SCS) or Cushing's syndrome (CS) based on the degree of cortisol hypersecretion. The molecular mechanisms driving hypercortisolism remain poorly understood. To address this, we perform comprehensive proteomic profiling of 9 CS, 10 SCS, and 10 non-functioning adenomas (NFAs). Our analysis reveals a central role for cholesterol metabolic reprogramming in the pathogenesis of CPAs. We observe a progressive gradient of dysregulation in cholesterol metabolic components from NFAs to SCS and CS, mirroring disease severity. A protein panel consisting of low density lipoprotein receptor (LDLR), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), hormone-sensitive lipase (LIPE), and synaptophysin (SYP) is identified as a promising combination of candidate pathological markers for CPAs. Importantly, downregulation of calcium binding protein 39 like (CAB39L) is uncovered as a key driver of pathological cortisol production. These findings provide a foundation for protein-based diagnostic and prognostic strategy in CPAs, and highlight the CAB39L signaling pathway as a contributor to disease development.