Macrophage pyroptosis drives luminal senescence and club-cell reprogramming in 5α-reductase inhibitor-treated
Zheng Li1, Zhenan Zhang2, Qiancheng Zhao1
1Department of Urology, Peking University First Hospital, Institute of Urology, Beijing Key Laboratory of Urogenital Diseases (Male), Molecular Diagnosis and Treatment Center., National Research Center for Genitourinary Oncology, Peking University, Beijing, China.
Abstract:
Benign prostatic hyperplasia (BPH) is a common age-associated disease whose prevalence rises sharply with advancing age. Therapeutic responses to 5α-reductase inhibitors (5-ARIs) in BPH are heterogeneous and may ultimately culminate in the need for surgery; however, the mechanisms that permit disease progression during treatment remain unclear. Here we integrate spatial and single-cell transcriptomics with functional perturbations and mouse genetics to delineate a macrophage-orchestrated pyroptosis-senescence-club axis in the human prostate. In 5-ARI-exposed tissue, we observe enrichment of cleaved-GSDMD⁺ macrophages, elevated epithelial p16INK4A expression and expansion of SCGB1A1⁺ club cells. Spatial mapping pinpoints macrophage-epithelium hotspots with prominent MIF-CD74 and HMGB1-AGER signaling. Under 5-ARI pressure, luminal-cell secretomes recruit macrophages via MIF-CD74, and pyroptotic macrophages release HMGB1 that activates epithelial AGER to trigger luminal G1 arrest and senescence, which in turn promotes luminal-to-club reprogramming through a partially Notch-associated program. Blockade of MIF-CD74 or HMGB1-AGER attenuates macrophage pyroptosis and luminal senescence, whereas Notch inhibition partially reverses epithelial remodeling. A 13-gene pyroptosis-macrophage signature (PM-13) stratifies patient responsiveness to 5-ARIs. In a castration/testosterone-induced mouse BPH model, 5-ARI treatment amplifies pyroptotic macrophages and club programs, whereas Gsdmd deletion blunts pyroptosis and dampens senescence/club transcriptional states. These findings nominate druggable nodes-MIF-CD74, HMGB1-AGER, Notch and GSDMD-as candidate targets for therapeutic intervention and patient stratification in BPH under 5-ARI therapy.Keywords: spatial and single-cell transcriptomics; benign prostatic hyperplasia; 5-alpha-reductase inhibitors; cellular senescence; macrophage pyroptosis; luminal-to-club conversion; MIF-CD74/HMGB1-AGER signaling; GSDMD.
