Spatial and single-cell transcriptomics reveal a HIF-1α/NF-κB-driven hypoxia-induced senescence axis in BPH...

Area of Science:

• Urology
• Cell Biology
• Molecular Biology

Background:

• Benign prostatic hyperplasia (BPH) is a common age-related condition with unclear underlying mechanisms.
• Understanding the cellular and molecular drivers of BPH is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of hypoxia-associated epithelial senescence in the pathogenesis of BPH.
• To elucidate the molecular pathways, including HIF-1α and NF-κB signaling, involved in BPH development.

Main Methods:

• Integrated multi-omics data (laser capture microdissection RNA sequencing, single-cell RNA sequencing, spatial transcriptomics) with human tissue validation and mouse models.
• Performed in vitro perturbation assays to assess the effects of modulating hypoxia and related signaling pathways.
• Analyzed senescence markers, hypoxia-inducible factor 1-alpha (HIF-1α), and nuclear factor kappa B (NF-κB) signaling.

Main Results:

• Hypoxia-associated epithelial senescence, characterized by increased HIF-1α, NF-κB activity, and senescence-associated secretory phenotype (SASP) gene expression, was identified in BPH.
• HIF-1α and NF-κB signaling were found to induce senescence phenotypes in epithelial cells and promote stromal cell proliferation.
• Inhibition of HIF-1α or NF-κB signaling attenuated BPH progression and associated cellular changes in both in vitro and in vivo models.

Conclusions:

• Hypoxia-driven HIF-1α and NF-κB signaling are key contributors to epithelial senescence and epithelial-stromal crosstalk in BPH.
• Targeting these pathways represents a potential therapeutic strategy for managing benign prostatic hyperplasia.