Targeting RBP4-STRA6 retinol signaling disrupts adipose-prostate crosstalk: A novel strategy to suppress basal cell plasticity in androgen deprivation.

Metabolic rewiring is a starter for lineage plasticity, which is an important driver of prostate development, tumorigenesis and treatment resistance. Androgen-targeted therapies are central to prostate cancer (PCa) management, yet the mechanisms leading prostate development-particularly the metabolic signaling within basal cells during treatment-remain poorly understood. To fulfill this gap, we used multiple models to reveal the metabolic alterations in prostate basal cells. Our study reveals the role of the RBP4-STRA6 axis in modulating retinol metabolism and transporting retinol from adipocyte into prostate cells, contributing to prostate development and basal cell differentiation during androgen deprivation. Through multi-omics analyses, we demonstrate that RBP4-STRA6 axis dependent retinol metabolism is increased with androgen deprivation. Retinol metabolism rewiring is modulated by the androgen receptor (AR) and can regulate basal cell plasticity under androgen deprivation therapy (ADT). Retinol metabolism maintains prostate basal cell lineage plasticity during hormone therapy through the PPARγ signaling pathway, compensating for the AR signaling pathway inhibition by sustaining energy homeostasis and promoting basal cell differentiation. Notably, we identified a basal cell cluster (BC5) characterized by high Retinol metabolism and activated PPARγ signaling pathway, which plays a crucial role in basal-luminal differentiation and prostate growth. This study underscores the importance of RBP4-STRA6 dependent Retinol metabolism, mediating the crosstalk between adipocytes and prostate basal cells, in maintaining prostate development during hormone therapy and provides a foundation for future clinical interventions and diet strategies aimed at enhancing the sensitivity of androgen deprivation in prostate diseases.