HSD3B1 links ileal steroid metabolism to bile acid regulation in patients with prostate cancer.

Androgen deprivation therapy (ADT), a cornerstone of advanced prostate cancer treatment, effectively suppresses androgen signaling but frequently induces systemic metabolic dysregulation. Here, we delineate an unrecognized intestinal steroid/bile acid regulatory axis that mechanistically links androgen suppression to extratumoral metabolic aberrations. HSD3B1 is the most common inherited link to prostate cancer mortality and mediates its effects by regulating steroid metabolism. Integrated metabolomic profiling of patients undergoing ADT revealed a rapid genotype-associated reduction in circulating bile acids, most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele. Surprisingly, analyses in human intestinal tissue and mechanistic investigations in in vitro models identified the terminal ileum as a unique site of HSD3B1 and SLC10A2 (ASBT) coexpression, where catalytically active 3βHSD1 is transcriptionally governed by liver receptor homolog-1 (LRH-1). Pharmacologic or genetic LRH-1 inhibition coordinately suppressed HSD3B1 and SLC10A2 expression and function, while inducing adaptive HSD11B2 upregulation and enhanced glucocorticoid inactivation. This LRH-1-dependent regulatory program persisted independently of androgen and glucocorticoid receptor signaling under in vitro conditions modeling androgen deprivation. These findings establish LRH-1 as a central integrator of intestinal steroidogenesis and bile acid transport and implicate the LRH-1/HSD3B1/SLC10A2 network as a mechanistic driver of ADT-associated metabolic disturbances and a potential target for therapeutic intervention.