Exploring glucocorticoid receptor signaling in lymphangioleiomyomatosis

ABSTRACT Background Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signaling might influence LAM biology and clinical features. Methods We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 −/− embryonic fibroblasts and human TSC2 −/− AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. Results In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift toward slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated ACTH and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiologic disease stage. AML cells showed elevated expression of POMC , which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Conclusions Our findings suggest that GR signaling may contribute to aspects of LAM cell behavior and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.