Benign prostatic hyperplasia (BPH) is an age-associated disorder characterized by nodular overgrowth in the prostatic transition zone and a leading cause of lower urinary tract symptoms. While androgen receptor (AR)–linked signaling has long framed BPH pathogenesis and treatment, a significant proportion of patients show limited response to androgen-targeted therapies and may ultimately require surgery. Traditional bulk molecular assays average signals across mixed cell populations and can obscure rare but biologically important cell subsets. Single-cell RNA sequencing (scRNA-seq) offers high-resolution profiling of transcriptomes at the single-cell level, enabling reconstruction of cell-state transitions, intercellular signaling networks, and the identification of discrete cellular contributors to disease. This technology therefore provides a means to move beyond an exclusively androgen-centric model and to clarify alternative, non-androgen-driven mechanisms relevant to BPH progression and treatment resistance.
scRNA-seq generates cellular atlases that compare normal prostate compartments with hyperplastic tissue. These single-cell maps reveal a heterogeneous cellular ecosystem in BPH composed of epithelial (luminal, basal and novel basal subsets), stromal (fibroblasts, smooth muscle, endothelial) and immune populations (macrophages, CD4+, CD8+, regulatory T cells, NK cells). Analyses emphasize the transition zone as the predominant site of nodular hyperplasia and show regional reconfiguration of cell subsets and transcriptional programs associated with disease.
Prostatic homeostasis reflects coordinated contributions of three major compartments: epithelium, stroma, and immune microenvironment. The epithelium is organized as luminal secretory cells, basal cells with stem/progenitor capacity, and scattered neuroendocrine cells. Luminal cells synthesize prostatic secretions; basal cells serve regenerative roles and maintain epithelial integrity. The stroma—fibroblasts, smooth muscle cells, endothelial cells and extracellular matrix—supports structure, paracrine signaling, and angiogenesis. The immune microenvironment balances tissue remodeling and surveillance through resident macrophages, T cells, dendritic cells and innate lymphoid populations; infiltrating immune subsets are associated with injury or inflammation. Understanding these baseline roles is essential for interpreting pathological shifts in BPH.
Single-cell studies highlight reconfiguration of epithelial-to-stromal ratios and the emergence or expansion of specific pathogenic cell subsets in BPH. A notable finding is a novel basal epithelial subtype (BE5) identified as an initiating cell for proliferative nodule formation and as a transitional intermediate in luminal-to-basal conversion. Fibroblast populations show subtype diversity and region-specific distributions; certain fibroblast subsets exhibit higher transcriptional activity in immune and proliferative pathways and lower androgen-lineage signaling, particularly in the transition zone. Immune cell composition also shifts, with macrophage subpopulations (including TREM2/MARCO–high cells) and lymphocyte subsets implicated in promoting hyperplasia.
scRNA-seq emphasizes several AR-independent drivers of BPH. Chronic inflammation and immune infiltration shape a proliferative microenvironment, and senescent cells with a senescence-associated secretory phenotype (SASP) perpetuate pro-proliferative signaling. An age-associated CD8+ T cell subset (Taa) secreting granzyme K has been linked to SASP induction in fibroblasts, which then amplifies CD8+ T cell infiltration and hyperplasia. Fibroblast activation, epithelial–mesenchymal transition (EMT) in subsets such as BE5, and altered immune–stromal crosstalk are central themes that account for disease progression independent of AR signaling.
Single-cell and complementary analyses nominate multiple signaling axes and molecules beyond the androgen pathway. Examples captured in single-cell-derived datasets or collated analyses include:
These findings point to candidate biomarkers and therapeutic targets beyond AR inhibition, although the review notes that detailed mechanistic validation remains necessary.
scRNA-seq clarifies mechanisms that may underlie resistance to androgen-targeted therapies and suggests microenvironment-targeted interventions. For example, finasteride can induce epithelial apoptosis yet paradoxically promote basal cell proliferation via TGF-β1 and EGFR/PCNA signaling, providing a potential explanation for therapeutic rebound or persistence. Immune and stromal signatures (e.g., TREM2/MARCO–high macrophages correlated with prostate volume and symptom score) offer candidate biomarkers for disease stratification. The review highlights the translational promise of molecular subtyping and spatial multi-omics to support precision therapies targeting inflammatory, senescent, or stromal drivers.
Although scRNA-seq has reshaped the conceptual framework for BPH, several challenges remain. Conflicting single-cell results—such as differing functional assignments for fibroblast subpopulations, the directionality of inflammatory causation, and the role of AR-negative cells—require reconciliation. The field lacks a standardized translational roadmap to map molecular subtypes to clinical indicators. The review advocates integrating scRNA-seq with spatial multi-omics and conventional methods to construct a spatiotemporal atlas of BPH, validate candidate mechanisms, and inform design of non-androgenic, microenvironment-targeted therapies.
scRNA-seq is redefining BPH as a heterogeneous, microenvironment-driven disorder in which chronic inflammation, senescence, stromal activation, and specific epithelial and immune subpopulations play central roles. By revealing AR-independent pathways and candidate targets (for example, CSF1/PI3K–Akt, CXCL13/CD4+ axis, granzyme K–SASP interactions), single-cell approaches offer a path toward molecular subtyping and precision therapies. Continued integration of single-cell data with spatial and functional validation is needed to translate these insights into clinical tools and non-androgenic therapeutic strategies.