Study identifies macrophage pyroptosis as driver of cellular senescence in 5-alpha-reductase inhibitor-treated prostatic hyperplasia

Researchers have mapped a macrophage-orchestrated pyroptosis-senescence axis in drug-resistant benign prostatic hyperplasia, identifying GSDMD, MIF-CD74, and HMGB1-AGER as potential therapeutic targets to halt tissue remodeling.

A study published in Experimental & Molecular Medicine reported that macrophage pyroptosis drives luminal cellular senescence and club-cell reprogramming in benign prostatic hyperplasia (BPH) tissues treated with 5-alpha-reductase inhibitors (5-ARIs).

By integrating single-cell and spatial transcriptomics, the researchers demonstrated that under 5-ARI pressure, luminal cells recruit macrophages via MIF-CD74 signaling.

The recruited pyroptotic macrophages release HMGB1, which activates epithelial AGER to trigger G1 cell-cycle arrest and p16INK4A-positive cellular senescence, subsequently promoting luminal-to-club cell reprogramming via a partially Notch-associated pathway.

In a castration/testosterone-induced mouse model, genetic deletion of Gsdmd or the blockade of MIF-CD74 and HMGB1-AGER pathways was reported to blunt macrophage pyroptosis, decrease epithelial senescence, and reverse cellular remodeling.

The authors proposed a 13-gene pyroptosis-macrophage signature (PM-13) that successfully stratified patient responsiveness to 5-ARI therapy in clinical datasets.

The findings provide a clear cellular and molecular explanation for the heterogeneous therapeutic responses and progression to surgery observed in BPH patients on long-term 5-ARI therapy.

By demonstrating that macrophage pyroptosis is the direct upstream trigger of epithelial senescence, the study identifies precise extracellular (MIF-CD74, HMGB1-AGER) and intracellular (GSDMD) nodes that can be targeted to break the pathology loop.

The research adds to the growing body of evidence showing that cellular senescence is not just an autonomous aging program but can be infectious, driven by immune-cell-derived secretory phenotypes.

This work widens the target landscape for anti-aging and senotherapeutic drug developers by establishing macrophage pyroptosis as an upstream instigator of localized senescent microenvironments.

Therapies aimed at macrophage reprogramming or neutralizing macrophage-derived alarmins (such as HMGB1) may find a secondary or primary market expansion in age-related urological diseases like BPH.

The development of the 13-gene pyroptosis-macrophage signature highlight opportunities for precision medicine developers to create companion diagnostics for patient stratification in age-related tissue hyperplasias.

Preclinical testing of selective GSDMD inhibitors or neutralizing antibodies targeting MIF-CD74 and HMGB1-AGER to evaluate efficacy in resolving established hyperplastic prostatic tissue.

Prospective clinical validation of the PM-13 gene signature to determine its utility in predicting 5-ARI therapeutic failure prior to surgical intervention.