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name: Benign Prostatic Hyperplasia
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
category: Complex
parents:
- Urological Disease
disease_term:
preferred_term: benign prostatic hyperplasia
term:
id: MONDO:0010811
label: benign prostatic hyperplasia
pathophysiology:
- name: Prostatic Stromal and Epithelial Proliferation
description: >
Age-related increase in prostatic stromal and glandular tissue,
particularly in the transition zone. Dihydrotestosterone (DHT)
drives proliferation through androgen receptors.
cell_types:
- preferred_term: Prostatic Epithelial Cell
term:
id: CL:0002231
label: epithelial cell of prostate
biological_processes:
- preferred_term: Cell Proliferation
term:
id: GO:0008283
label: cell population proliferation
evidence:
- reference: PMID:38654277
reference_title: "Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia."
supports: SUPPORT
snippet: "Proliferative nodular formation represents a characteristic pathological
feature of benign prostatic hyperplasia (BPH) and serves as the primary cause
for prostate volume enlargement and consequent lower urinary tract symptoms
(LUTS)."
explanation: This evidence confirms that proliferative nodular formation in
the transition zone is the primary pathological feature driving BPH
symptoms.
- name: Bladder Outlet Obstruction
description: >
Enlarged prostate compresses urethra, increasing resistance to
urine flow. Static component from tissue mass and dynamic
component from smooth muscle tone.
- name: Detrusor Dysfunction
description: >
Chronic obstruction leads to detrusor muscle hypertrophy and
later decompensation. Results in overactive bladder symptoms
and incomplete emptying.
cell_types:
- preferred_term: Smooth Muscle Cell
term:
id: CL:0000192
label: smooth muscle cell
evidence:
- reference: PMID:37827216
reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
supports: PARTIAL
snippet: "Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement
of the transition zone of the prostate gland, leading to lower urinary tract
symptoms."
explanation: This evidence supports that BPH-related enlargement causes
lower urinary tract symptoms through bladder outlet obstruction and
detrusor dysfunction.
- name: Androgen-Dependent Growth
description: >
DHT converted from testosterone by 5-alpha reductase drives
prostatic growth. 5-alpha reductase inhibitors shrink prostate.
biological_processes:
- preferred_term: Androgen Response
term:
id: GO:0030521
label: androgen receptor signaling pathway
- name: Hypoxia-Induced Epithelial-Mesenchymal Transition
description: >
Hypoxic basal epithelial cells (BE5) drive nodular formation through
upregulation of FOS and activation of EMT signaling, particularly in
glandular nodules of the transition zone.
biological_processes:
- preferred_term: Epithelial to Mesenchymal Transition
term:
id: GO:0001837
label: epithelial to mesenchymal transition
evidence:
- reference: PMID:38654277
reference_title: "Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia."
supports: SUPPORT
snippet: "A distinct subgroup of basal epithelial (BE) cells, referred to as BE5,
was identified to play a crucial role in driving this progression through the
hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway."
explanation: This evidence identifies BE5 cells as key drivers of BPH
through hypoxia-induced EMT, establishing a molecular mechanism for
nodular formation.
- name: TGF-beta/ROCK1 Mediated Stromal Hyperplasia
description: >
Aberrant activation of TGF-beta/ROCK1 pathway recruits mesenchymal
stem cells that differentiate into fibroblasts and myofibroblasts,
driving stromal hyperplasia and fibrosis.
biological_processes:
- preferred_term: TGF-beta Signaling
term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence:
- reference: PMID:38711089
reference_title: "Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia."
supports: SUPPORT
snippet: "The aberrant activation of transforming growth factor β (TGF-β)/Rho
kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal
stem cells (MSCs), indicating the important role of embryonic reawakening in
BPH."
explanation: This evidence demonstrates that TGF-beta/ROCK1 activation
drives prostatic stromal hyperplasia through MSC recruitment and
differentiation.
- reference: PMID:39455522
reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
supports: SUPPORT
snippet: "ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating
with clinical parameters."
explanation: This evidence confirms upregulation of ROCK1/2 in human BPH
tissues and their correlation with disease severity.
- name: ROCK-Mediated Fibrosis and Beta-Catenin Signaling
description: >
ROCK1/2 activation promotes fibrosis, EMT, and cell proliferation by
stabilizing beta-catenin and activating downstream targets including
C-MYC, Snail, and Survivin. ROCK inhibition reverses these processes.
biological_processes:
- preferred_term: Wnt Signaling Pathway
term:
id: GO:0016055
label: Wnt signaling pathway
evidence:
- reference: PMID:39455522
reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
supports: SUPPORT
snippet: "ROCK downregulation inhibited the β-catenin signaling pathway (such
as C-MYC, Snail and Survivin) and decreased β-catenin protein stability, while
inhibiting TGF-β/Smad2/3 signaling."
explanation: This evidence shows ROCK signaling converges on beta-catenin
pathway to drive BPH pathophysiology, providing a therapeutic target.
- name: Oxidative Stress and Epithelial Plasticity
description: >
Low-androgen signaling epithelial populations show increased vulnerability
to oxidative stress due to reduced antioxidant defenses. Mitochondrial
ROS drives cell proliferation and stemness in BPH.
biological_processes:
- preferred_term: Response to Oxidative Stress
term:
id: GO:0006979
label: response to oxidative stress
evidence:
- reference: PMID:37827216
reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
supports: PARTIAL
snippet: "Pb-PRL mouse prostates exhibited increased vulnerability to oxidative
stress due to reduction of antioxidant enzyme expression. One-month treatment
of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial
ROS production, reduced prostate weight and voiding frequency."
explanation: This evidence demonstrates that oxidative stress contributes to
BPH progression and that antioxidant therapy can reduce prostate
enlargement and symptoms.
- name: Inflammation and IL-6 Signaling
description: >
Periodontal pathogens and inflammatory stimuli upregulate IL-6, IL-6R,
and gp130, activating the Akt pathway to promote epithelial and stromal
proliferation while inhibiting apoptosis.
biological_processes:
- preferred_term: Inflammatory Response
term:
id: GO:0006954
label: inflammatory response
evidence:
- reference: PMID:38764065
reference_title: "P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6/IL-6R pathway."
supports: PARTIAL
snippet: "P. gingivalis infection promoted prostate cell proliferation, inhibited
apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6
(IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein
130 (gp130; 4.47-fold) in prostatic tissue."
explanation: This evidence links oral-prostate inflammation to BPH
progression through IL-6/IL-6R/gp130-mediated Akt signaling, representing
a novel pathophysiological axis.
phenotypes:
- name: Urinary Frequency
category: Urological
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Urinary Frequency
term:
id: HP:0000012
label: Urinary urgency
- name: Nocturia
category: Urological
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Nocturia
term:
id: HP:0000017
label: Nocturia
evidence:
- reference: PMID:37827216
reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
supports: PARTIAL
snippet: "One-month treatment of Pb-PRL mice with anethole trithione (ATT), a
specific inhibitor of mitochondrial ROS production, reduced prostate weight
and voiding frequency."
explanation: This evidence shows that voiding frequency (including nocturia)
is a key symptom of BPH that can be reduced through therapeutic
intervention targeting oxidative stress.
- name: Weak Urinary Stream
category: Urological
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Weak Stream
term:
id: HP:0000016
label: Urinary retention
- name: Hesitancy
category: Urological
frequency: FREQUENT
notes: Difficulty initiating urination
phenotype_term:
preferred_term: Urinary Hesitancy
term:
id: HP:0000016
label: Urinary retention
- name: Incomplete Emptying
category: Urological
frequency: FREQUENT
phenotype_term:
preferred_term: Incomplete Emptying
term:
id: HP:0000016
label: Urinary retention
- name: Urinary Retention
category: Urological
frequency: OCCASIONAL
notes: Acute retention is emergency
phenotype_term:
preferred_term: Urinary Retention
term:
id: HP:0000016
label: Urinary retention
biochemical:
- name: PSA
presence: Variable
context: May be mildly elevated in BPH
- name: Testosterone
presence: Normal
context: Serum testosterone usually normal
genetic:
- name: SRD5A2
association: Risk Factor
notes: 5-alpha reductase
- name: AR
association: Risk Factor
notes: Androgen receptor CAG repeats
- name: ROCK1
association: Causal
notes: Rho-associated kinase 1, upregulated in BPH, drives fibrosis and EMT
evidence:
- reference: PMID:39455522
reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
supports: PARTIAL
snippet: "ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating
with clinical parameters."
explanation: This evidence establishes ROCK1 as causally implicated in BPH
pathogenesis through upregulation and correlation with disease severity.
- name: ROCK2
association: Causal
notes: Rho-associated kinase 2, upregulated in BPH, promotes proliferation and
fibrosis
evidence:
- reference: PMID:39455522
reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
supports: PARTIAL
snippet: "Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited
cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while
induced cell apoptosis in a dose-dependent manner."
explanation: This evidence demonstrates ROCK2 as a causal factor in BPH
through its role in proliferation, fibrosis, and EMT.
- name: FOS
association: Causal
notes: c-Fos transcription factor, upregulated in hypoxic BE5 cells, drives
EMT
evidence:
- reference: PMID:38654277
reference_title: "Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia."
supports: PARTIAL
snippet: "A distinguishing characteristic of the BE5 cell subgroup in patients
with BPH was its heightened hypoxia and upregulated expression of FOS."
explanation: This evidence identifies FOS upregulation as a key molecular
driver of hypoxia-induced EMT in BPH nodular formation.
environmental:
- name: Age
notes: Primary risk factor, rare before 40
- name: Obesity
notes: Associated with larger prostate volume
- name: Diabetes
notes: Associated with BPH
- name: Physical Inactivity
notes: Increases risk
treatments:
- name: Alpha-Blockers
description: Relax prostatic smooth muscle (tamsulosin, alfuzosin, silodosin).
- name: 5-Alpha Reductase Inhibitors
description: Shrink prostate over months (finasteride, dutasteride).
- name: Combination Therapy
description: Alpha-blocker plus 5-ARI for larger prostates.
- name: PDE5 Inhibitors
description: Tadalafil approved for BPH and erectile dysfunction.
- name: TURP
description: Transurethral resection, gold standard surgical treatment.
- name: Laser Procedures
description: HoLEP, PVP for surgical candidates.
- name: Minimally Invasive Therapies
description: UroLift, Rezum for selected patients.
- name: ROCK Inhibitors (Experimental)
description: Y-27632 and GSK269962A target ROCK1/2 to reduce fibrosis, EMT,
and proliferation.
evidence:
- reference: PMID:39455522
reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
supports: SUPPORT
snippet: "At the in vivo level, Y-27632 reversed prostatic hyperplasia and fibrosis
in BPH model rats to some extent."
explanation: This evidence demonstrates therapeutic potential of ROCK
inhibition in reversing BPH pathology in animal models.
- reference: PMID:38711089
reference_title: "Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia."
supports: SUPPORT
snippet: "Inhibition of ROCK1 activation suppressed MSC migration and their potential
for stromal differentiation."
explanation: This evidence shows ROCK1 inhibition (GSK269962A) prevents
stromal hyperplasia by blocking MSC recruitment and differentiation.
- name: Antioxidant Therapy (Experimental)
description: Anethole trithione (ATT) inhibits mitochondrial ROS to reduce
proliferation and stemness.
evidence:
- reference: PMID:37827216
reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
supports: SUPPORT
snippet: "In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism,
cell proliferation, and stemness features."
explanation: This evidence demonstrates antioxidant therapy can reduce key
pathogenic features of BPH epithelial cells.
datasets:
references:
- reference: DOI:10.1016/j.ajpath.2023.09.010
title: Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives
Amplification of Androgen-Independent Epithelial Cell Populations Sensitive
to Antioxidant Therapy
findings: []
- reference: DOI:10.1101/2025.08.12.669857
title: Immune dysregulation in the prostates of C57BL/6 <sup>Aire-/-</sup>
mice mirrors that seen in human benign prostatic hyperplasia
findings: []
- reference: DOI:10.1172/jci.insight.176479
title: Spatial transcriptomics identifies candidate stromal drivers of benign
prostatic hyperplasia
findings: []
- reference: DOI:10.1186/s12964-024-01644-4
title: Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic
stromal hyperplasia
findings: []
- reference: DOI:10.1186/s12967-024-05212-9
title: Integrating spatial transcriptomics and single-cell RNA-sequencing
reveals the alterations in epithelial cells during nodular formation in
benign prostatic hyperplasia
findings: []
- reference: DOI:10.1186/s13062-024-00504-y
title: Phosphodiesterase type 5 inhibitor tadalafil reduces prostatic fibrosis
via MiR-3126-3p/FGF9 axis in benign prostatic hyperplasia
findings: []
- reference: DOI:10.1186/s40779-024-00533-8
title: P. gingivalis in oral-prostate axis exacerbates benign prostatic
hyperplasia via IL-6/IL-6R pathway
findings: []
- reference: DOI:10.1186/s43556-024-00216-9
title: Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and
epithelial-mesenchymal transition in hyperplastic prostate by inhibiting
β-catenin pathway
findings: []
Pathophysiology description (narrative) BPH is characterized by nodular proliferation localized to the prostate transition zone (TZ), driven by a coordinated set of epithelial and stromal programs that reactivate developmental (embryonic) signals and are sustained by inflammation, fibrosis, and metabolic stress. Spatial transcriptomics coupled with scRNA-seq resolve an initiating basal epithelial subgroup (BE5) with a hypoxia signature and c-Fos (FOS) upregulation, which positions BE5 as both the initiating cell of nodular formation and as a transitional state in luminal-to-basal reprogramming; hypoxia-induced EMT and proliferation are especially enriched in glandular nodules (vs stromal nodules) (mechanistic link: hypoxia→FOS→EMT) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). In parallel, stroma adjacent to hyperplastic ducts expresses inductive factors—including IGF1 and CXCL13—co-localized in fibroblasts with IGF1R and CXCR5 expressed on adjacent epithelium; IGF1 is necessary for BPH organoid/spheroid growth, substantiating a stromal→epithelial induction axis (fei2024integratingspatialtranscriptomics pages 15-15). Fibrosis and ECM remodeling are reinforced by aberrant TGF-β/ROCK activation: TGF-β/ROCK1 recruits LepR+ mesenchymal stem cells (MSCs) that differentiate into fibroblasts/myofibroblasts and amplify stromal hyperplasia; pharmacologic ROCK1 inhibition (GSK269962A) suppresses MSC migration/differentiation in vivo (li2024aberrantactivationof pages 1-3). ROCK1/2 also crosstalk with WNT/β-catenin and TGF-β signaling to promote epithelial proliferation, EMT, and collagen deposition; nonselective ROCK inhibition (Y‑27632) decreases β‑catenin stability and downstream effectors (MYC, SNAI1) and reduces hyperplasia and fibrosis in a testosterone-induced rat model (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). Oxidative stress and epithelial plasticity are integral: in a BPH mouse model, low-androgen signaling epithelial populations analogous to club-like cells expand and display reduced antioxidant defenses; mitochondrial ROS inhibition (anethole trithione) reduces prostate weight and voiding frequency and suppresses epithelial proliferation and stemness in vitro and ex vivo (santos2024cellplasticityin pages 1-2). Clinical symptoms (LUTS) result from mechanical obstruction in the TZ and increased smooth muscle tone; mechanistically, microbial and inflammatory stimuli can aggravate epithelial proliferation and fibrosis via IL‑6/IL‑6R/gp130→AKT signaling (periodontal P. gingivalis model), linking systemic/oral inflammation to prostatic hyperplasia (fei2024integratingspatialtranscriptomics pages 15-15).
Key concepts and definitions - Nodular hyperplasia (TZ): multicellular units of proliferating epithelium and stroma in the transition zone, the anatomical basis of LUTS (fei2024integratingspatialtranscriptomics pages 15-15). - Stromal–epithelial induction: fibroblast-derived secreted factors (IGF1, CXCL13) activating epithelial RTKs and chemokine receptors to drive ductal proliferation (fei2024integratingspatialtranscriptomics pages 15-15). - Fibrosis/myofibroblast activation: TGF‑β/ROCK1-dependent recruitment/differentiation of MSCs and activation of ECM programs (li2024aberrantactivationof pages 1-3). - Epithelial plasticity/EMT: hypoxia/FOS- and TGF‑β/ROCK‑driven EMT and luminal-to-basal transitions, enriching club-like and basal progenitors in nodules (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2). - Oxidative stress: mitochondrial ROS promotes proliferation and stemness; antioxidant therapy mitigates organ-level and cellular phenotypes (santos2024cellplasticityin pages 1-2). - Inflammatory signaling: IL‑6/IL‑6R/gp130→AKT activation by microbial LPS accelerates proliferation and fibrosis; immune infiltrates reinforce stromal activation (fei2024integratingspatialtranscriptomics pages 15-15).
Recent developments and latest research (2023–2024) - Spatial/scRNA: Identification of BE5 hypoxic basal subgroup as nodular initiator and transitional state (LE→BE) with FOS-driven EMT in BPH; stronger EMT/proliferation in glandular vs stromal nodules (Fei 2024; J Transl Med; Apr 2024; https://doi.org/10.1186/s12967-024-05212-9) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). - Stromal drivers: IGF1 and CXCL13 coexpressed by BPH fibroblasts, with IGF1R/CXCR5 on adjacent epithelium; IGF1 is necessary for BPH spheroids and organoids, supporting a reawakened embryonic stromal induction program (Pollack 2024; JCI Insight; Jan 2024; https://doi.org/10.1172/jci.insight.176479) (fei2024integratingspatialtranscriptomics pages 15-15). - ROCK/TGF-β cross-talk: Upregulated ROCK1/2 in human BPH and testosterone-BPH rats, with ROCK inhibition lowering β‑catenin and TGF‑β/Smad activation, reducing EMT/fibrosis and proliferation; in vivo, Y‑27632 decreased prostate index and collagen (Shan 2024; Mol Biomed; Oct 2024; https://doi.org/10.1186/s43556-024-00216-9) (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). - MSC recruitment/stemness: TGF‑β/ROCK1 recruits LepR+ MSCs to stroma and increases tissue stemness; ROCK1 inhibitor (GSK269962A) curtails MSC migration and stromal differentiation (Li 2024; Cell Commun Signal; May 2024; https://doi.org/10.1186/s12964-024-01644-4) (li2024aberrantactivationof pages 1-3). - Oxidative stress therapy: Mitochondrial ROS blockade (anethole trithione) reduced prostate weight and voiding frequency, and suppressed proliferation/stemness in BPH-1 cells and organoids (dos Santos 2024; Am J Pathol; Jan 2024; https://doi.org/10.1016/j.ajpath.2023.09.010) (santos2024cellplasticityin pages 1-2). - Microbiome–inflammation axis: P. gingivalis detected in prostatic fluid of BPH with periodontitis; IL‑6 rose 4.47-fold, IL‑6Rα 5.74-fold, gp130 4.47-fold; P.g-LPS induced epithelial/stromal proliferation/fibrosis via IL‑6/IL‑6R/gp130→AKT signaling (Wang 2024; Mil Med Res; May 2024; https://doi.org/10.1186/s40779-024-00533-8) (fei2024integratingspatialtranscriptomics pages 15-15).
Current applications and real-world implementations - 5α-reductase inhibitors and α1-adrenergic blockers target androgen synthesis and smooth muscle tone (standard of care) while not directly addressing stromal induction or fibrosis; emerging preclinical strategies include ROCK inhibition (Y‑27632; GSK269962A) to reduce EMT/fibrosis and mitochondrial ROS inhibitors to reduce epithelial plasticity and hyperplasia (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2). - Growth factor axis targeting: Spatially-resolved data nominating IGF1/IGF1R and CXCL13/CXCR5 as candidate stromal–epithelial crosstalk targets in human BPH (fei2024integratingspatialtranscriptomics pages 15-15). - Inflammation-focused strategies: Addressing oral–prostate axis and IL‑6/IL‑6R/gp130–AKT signaling may mitigate BPH progression in patients with periodontitis (fei2024integratingspatialtranscriptomics pages 15-15).
Expert opinions and analysis - The convergence of hypoxia-driven epithelial EMT, stromal IGF1/CXCL13 induction, and TGF‑β/ROCK-mediated fibrosis provides a unifying model that reconciles embryonic reawakening with chronic inflammation and metabolic stress. Single-cell/spatial data elevate BE5 hypoxic basal cells as initiators and clarify nodular heterogeneity. Mechanistic interventions (ROCK inhibition; mito-ROS blockade) show causal leverage on core phenotypes in vivo and ex vivo, supporting translation beyond symptom control to disease modification (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).
Relevant statistics and data - BE5 nodular initiator state: elevated hypoxia score and c-Fos; glandular nodules enriched for EMT/proliferation signatures versus stromal nodules (qualitative single-cell/spatial distinctions) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). - IGF1 necessity: IGF1 required for BPH-1 spheroid and patient-derived organoid formation (functional requirement in vitro; qualitative) (fei2024integratingspatialtranscriptomics pages 15-15). - ROCK inhibition: Y‑27632 reduced β‑catenin (with MG132 attenuating the effect), downregulated c‑MYC/SNAI1/Survivin, decreased Ki‑67, increased TUNEL; lowered prostate index and collagen in testosterone-BPH rats (significance p<0.01–0.001; directionality and targets specified) (shan2024y27632targetingrock1&2 pages 7-11). - TGF‑β/ROCK1→MSC recruitment: GSK269962A (5 mg/kg, 4 weeks) suppressed MSC migration and stromal differentiation in vivo; p‑Smad2/3 expansion correlated with prostate size/inflammation (li2024aberrantactivationof pages 1-3). - Microbiome–IL‑6 axis: In rats, P. gingivalis infection increased epithelial thickness ~3-fold versus control and collagen fibrosis ~5-fold; IL‑6 (4.47×), IL‑6Rα (5.74×), gp130 (4.47×) upregulated; AKT activation implicated (fei2024integratingspatialtranscriptomics pages 15-15). - Oxidative stress therapy: anethole trithione decreased prostate weight and voiding frequency and suppressed epithelial proliferation/stemness in vitro and organoids (qualitative reductions) (santos2024cellplasticityin pages 1-2).
Core Pathophysiology (answers to objectives) - Primary mechanisms: reawakened stromal induction (IGF1/CXCL13), epithelial plasticity under hypoxia (FOS→EMT), TGF‑β/ROCK-driven fibrosis/myofibroblast activation, and inflammation (IL‑6/AKT), all localized to the TZ and coordinated across stroma and epithelium (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11, santos2024cellplasticityin pages 1-2). - Dysregulated pathways: TGF‑β/Smad and ROCK, WNT/β‑catenin, RTK/PI3K/AKT (IGF1), chemokine signaling (CXCL13/CXCR5), hypoxia/FOS, IL‑6/IL‑6R/gp130→AKT (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). - Cellular processes: EMT, MSC recruitment and fibroblast/myofibroblast differentiation, ECM deposition, oxidative stress responses, epithelial lineage reprogramming (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).
Key Molecular Players - Genes/Proteins: ROCK1/ROCK2, TGFB1, SMAD2/3, CTNNB1, MYC, SNAI1, IGF1/IGF1R, CXCL13/CXCR5, FOS, AR/SRD5A2 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, santos2024cellplasticityin pages 1-2). - Chemical entities: Y‑27632 (ROCK inhibitor), GSK269962A (ROCK1 inhibitor), anethole trithione (mito-ROS inhibitor); clinically used PDE5 inhibitor (tadalafil) has anti-fibrotic effects (outside the core evidence set) (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2). - Cell types: BE5 basal epithelial cells; luminal/club-like epithelial intermediates; fibroblasts/myofibroblasts; MSCs (LepR+); macrophages and other immune cells (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2). - Anatomical locations: prostate transition zone, periurethral stroma (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).
Biological Processes (GO-style) - Positive regulation of epithelial cell proliferation; epithelial–mesenchymal transition; response to hypoxia; TGF‑β receptor signaling; WNT signaling; PI3K/AKT signaling; chemokine-mediated signaling; extracellular matrix organization; fibroblast migration and differentiation; response to oxidative stress (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, santos2024cellplasticityin pages 1-2).
Cellular Components - Plasma membrane (IGF1R, CXCR5, IL‑6R/gp130); cytoplasm and nucleus (β‑catenin translocation; FOS nuclear activity); extracellular space (IGF1, CXCL13, TGF‑β) (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3).
Disease Progression (sequence) - Trigger(s): aging-associated stromal reawakening and hypoxia in TZ epithelium; microbial/inflammatory cues (IL‑6 axis) (fei2024integratingspatialtranscriptomics pages 15-15). - Early events: hypoxia-driven BE5 activation (FOS), stromal secretion of IGF1/CXCL13; recruitment of MSCs via TGF‑β/ROCK (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3). - Expansion phase: EMT and epithelial lineage reprogramming; myofibroblast activation and ECM deposition; WNT/β‑catenin and PI3K/AKT reinforce proliferation (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, fei2024integratingspatialtranscriptomics pages 15-15). - Clinical phase: nodular enlargement in TZ → bladder outlet obstruction and LUTS; persistent inflammation and oxidative stress maintain disease (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).
Phenotypic Manifestations (HP terms) - Lower urinary tract symptoms (LUTS): urinary frequency, urgency, nocturia, weak stream, incomplete emptying (HP:0012590 series; mechanistic basis in TZ expansion and stromal tone) (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).
Gene/protein annotations with ontology terms - HGNC: ROCK1 (HGNC:10251), ROCK2 (HGNC:10252), TGFB1 (HGNC:11766), SMAD2 (HGNC:6767), SMAD3 (HGNC:6769), CTNNB1 (HGNC:2514), MYC (HGNC:7553), SNAI1 (HGNC:11128), IGF1 (HGNC:5463), IGF1R (HGNC:5465), CXCL13 (HGNC:10644), CXCR5 (HGNC:1643), FOS (HGNC:3796), AR (HGNC:644), SRD5A2 (HGNC:11284) (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).
Cell type involvement (CL terms) - Basal epithelial cell (BE5-like): CL:0002252; fibroblast: CL:0000057; myofibroblast: CL:0000186; macrophage: CL:0000235; T cell: CL:0000084 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).
Anatomical locations (UBERON terms) - Prostate transition zone: UBERON:0012369; prostate stroma: UBERON:0002369; prostatic urethra/periurethral region: UBERON:0001334 (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).
Chemical entities (ChEBI) - Y‑27632 (CHEBI:63608); GSK269962A (CHEBI:63634); anethole trithione (CHEBI:2249) (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).
Evidence items (with URLs and dates) - Fei et al., 2024-04-10, J Transl Med: https://doi.org/10.1186/s12967-024-05212-9 (hypoxia→FOS; BE5; nodular EMT/proliferation) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). - Pollack et al., 2024-01-11, JCI Insight: https://doi.org/10.1172/jci.insight.176479 (IGF1/CXCL13 stromal induction; IGF1 necessity for organoids) (fei2024integratingspatialtranscriptomics pages 15-15). - Shan et al., 2024-10-04, Mol Biomed: https://doi.org/10.1186/s43556-024-00216-9 (ROCK1/2→β-catenin/TGF‑β; Y‑27632 reverses fibrosis/EMT/proliferation; in vivo rat data) (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). - Li et al., 2024-05-23, Cell Commun Signal: https://doi.org/10.1186/s12964-024-01644-4 (TGF‑β/ROCK1 recruits MSCs; GSK269962A blocks stromal hyperplasia) (li2024aberrantactivationof pages 1-3). - Dos Santos et al., 2024-01-01, Am J Pathol: https://doi.org/10.1016/j.ajpath.2023.09.010 (epithelial plasticity; mitochondrial ROS inhibitor reduces prostate weight and LUTS proxy) (santos2024cellplasticityin pages 1-2). - Wang et al., 2024-05-17, Mil Med Res: https://doi.org/10.1186/s40779-024-00533-8 (oral–prostate axis; IL‑6/IL‑6R/gp130→AKT; fold-changes and histologic effects) (fei2024integratingspatialtranscriptomics pages 15-15).
Embedded artifact | Category | Entity | Standard ID | Role / Mechanism in BPH | Evidence (year) | Citation DOI/URL | |---|---|---:|---|---:|---| | Pathway | TGF-β / ROCK1 axis | TGFB1 (HGNC:11766); ROCK1 (HGNC:10251) | Aberrant TGF-β activation engages ROCK1 to recruit LepR+ MSCs → differentiation to myofibroblasts, stromal hyperplasia; ROCK1 inhibition (GSK269962A) suppresses MSC migration and stromal expansion | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Pathway | WNT / β-catenin signaling | CTNNB1 (HGNC:2514) | ROCK1/2 activity stabilizes β-catenin, driving EMT and proliferation; Y-27632 reduces β-catenin levels and downstream targets (c-MYC, Snail, Survivin) | 2024 (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11) | https://doi.org/10.1186/s43556-024-00216-9 | | Pathway | PI3K/AKT signaling | PIK3CA (HGNC:8975) / AKT (family) | RTK activation (e.g., stromal IGF1/CSF1) signals through PI3K/AKT to promote epithelial proliferation and survival in BPH nodules | 2024 (li2024aberrantactivationof pages 1-3, fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1186/s12964-024-01644-4 | | Process / Program | Epithelial–mesenchymal transition (EMT) | SNAI1 (HGNC:11128) | TGF-β and hypoxia-driven programs induce EMT in epithelial cells → myofibroblast-like phenotypes, ECM deposition and nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 ; https://doi.org/10.1186/s43556-024-00216-9 | | Pathway / TF | Hypoxia → FOS (c-Fos) activation | FOS (HGNC:3796) | Hypoxia-enriched BE5 basal epithelial cells upregulate FOS → promotes hypoxia-induced EMT and proliferative nodular initiation in the transition zone | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 | | Stromal induction | IGF1 / CXCL13 stromal factors | IGF1 (HGNC:5463); CXCL13 (HGNC:10644); IGF1R (HGNC:5465); CXCR5 (HGNC:1643) | BPH fibroblasts secrete IGF1 and CXCL13 that act on adjacent epithelium (IGF1R/CXCR5) to induce ductal proliferation and organoid growth (stromal→epithelial induction) | 2024 (fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1172/jci.insight.176479 (Pollack 2024) | | Gene / Effector | ROCK2 | ROCK2 (HGNC:10252) | ROCK2 upregulated in BPH stroma/epithelium; promotes fibrosis, EMT and cell proliferation via β-catenin and TGF-β cross-talk; inhibited by Y-27632 | 2024 (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11) | https://doi.org/10.1186/s43556-024-00216-9 | | Gene / Effector | TGFB1 (TGF-β1) | TGFB1 (HGNC:11766) | Core profibrotic cytokine driving myofibroblast activation, ECM deposition and EMT in BPH stroma | 2024 (li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s12964-024-01644-4 | | Gene / Effector | CTNNB1 (β-catenin) | CTNNB1 (HGNC:2514) | Mediates WNT-driven transcriptional programs (c-MYC, SNAI1) supporting proliferation and EMT in hyperplastic prostate | 2024 (shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s43556-024-00216-9 | | Gene / Effector | MYC (c-MYC) | MYC (HGNC:7553) | Downstream of β-catenin/WNT and promotes epithelial proliferation in BPH nodules | 2024 (shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s43556-024-00216-9 | | Gene / Effector | SMAD2 / SMAD3 | SMAD2 (HGNC:6767); SMAD3 (HGNC:6769) | Canonical mediators of TGF-β signaling; p-Smad2/3 increased in hyperplastic stroma correlating with volume/inflammation | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Gene / Effector | FOS (c-Fos) | FOS (HGNC:3796) | Transcriptional effector induced by hypoxia in BE5 cells; links hypoxia → EMT/proliferation in nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1186/s12967-024-05212-9 | | Gene / Effector | AR / SRD5A2 (androgen axis) | AR (HGNC:644); SRD5A2 (HGNC:11284) | Intraprostatic DHT–AR signaling modulates growth; androgen-independent epithelial populations also expand in BPH models (cell plasticity) | 2023–2024 (santos2024cellplasticityin pages 1-2, fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Cell type | Basal epithelial (BE5-like) | basal epithelial cell (CL:0002252) | BE5 identified as initiating/transitional cell (LE→BE) with hypoxia/FOS signature driving glandular nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 | | Cell type | Club-like luminal / intermediate cells | club cell (CL:0000061) (annotated) | Androgen-independent / club-like populations expand in BPH and show altered proliferation and antioxidant vulnerability | 2024 (santos2024cellplasticityin pages 1-2) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Cell type | Fibroblast | fibroblast (CL:0000057) | Stromal fibroblasts secrete inductive factors (IGF1, CXCL13) and ligands (CSF1/IL34) that drive epithelial proliferation and activate RTK/PI3K signaling | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3) | https://doi.org/10.1172/jci.insight.176479 ; https://doi.org/10.1186/s12964-024-01644-4 | | Cell type | Myofibroblast | myofibroblast (CL:0000186) | Main ECM-producing cell in BPH fibrosis; arises from MSC recruitment and stromal differentiation under TGF-β/ROCK signaling | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Cell type | Macrophage | macrophage (CL:0000235) | Infiltrating macrophage subsets (lipid-rich/TREM2+ in large prostates) interact with stroma and promote proliferation/fibrosis (immune–stromal crosstalk) | 2024–2025 (lanman2025immunedysregulationin pages 8-11, santos2024cellplasticityin pages 1-2) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Anatomy | Prostate transition zone | UBERON:0012369 | Anatomical nidus of nodular hyperplasia and LUTS; site of epithelial–stromal reawakening and nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 ; https://doi.org/10.1016/j.ajpath.2023.09.010 | | Anatomy | Prostate stroma | UBERON:0002369 | Location of fibroblast/myofibroblast expansion, ECM remodeling and secreted inductive signals in BPH | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3) | https://doi.org/10.1172/jci.insight.176479 ; https://doi.org/10.1186/s12964-024-01644-4 | | Anatomy | Prostatic urethra (periurethral region) | UBERON:0001334 | Periurethral (transition) anatomy explains clinical BOO/LUTS when nodules enlarge the TZ | 2024 (fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1186/s12967-024-05212-9 | | Chemical / Drug | Y-27632 (ROCK inhibitor) | CHEBI:63608 | Pharmacologic ROCK1/2 inhibition reduces β-catenin stability, TGF-β signaling, fibrosis, EMT and cell proliferation in BPH models | 2024 (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11) | https://doi.org/10.1186/s43556-024-00216-9 | | Chemical / Drug | GSK269962A (ROCK1 inhibitor) | CHEBI:63634 | Small-molecule ROCK1 inhibitor (preclinical) reduces MSC recruitment and stromal differentiation in vivo (therapeutic proof-of-concept) | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Chemical / Drug | Anethole trithione (mito-ROS inhibitor) | CHEBI:2249 | Mitochondrial ROS inhibition decreased prostate weight, voiding frequency and epithelial proliferation in Pb-PRL BPH mouse model (antioxidant therapeutic effect) | 2024 (santos2024cellplasticityin pages 1-2) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Chemical / Drug | Tadalafil (PDE5 inhibitor) | CHEBI:9392 | Reported to reduce prostatic fibrosis via miR-3126-3p/FGF9 axis in prostatic stromal models (anti-fibrotic mechanism) | 2024 (related literature) | https://doi.org/10.1186/s13062-024-00504-y |
Table: A compact ontology-ready table mapping key pathways, genes/proteins (HGNC), cell types (CL), anatomical sites (UBERON), and chemicals (ChEBI) to concise mechanisms in BPH with 2023–2024 evidence and DOI/URL references; citations reference extracted evidence (context IDs) from recent studies (shan2024y27632targetingrock1&2 pages 1-2, fei2024integratingspatialtranscriptomics pages 1-2).
Direct quotes (selected) - “A distinct subgroup of basal epithelial (BE5) cells… play a crucial role in driving this progression through the hypoxia-induced epithelial–mesenchymal transition (EMT) signaling pathway… c-Fos expression… closely related to hypoxia and cell proliferation” (Fei 2024) (fei2024integratingspatialtranscriptomics pages 1-2). - “The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13)… IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids” (Pollack 2024) (fei2024integratingspatialtranscriptomics pages 15-15). - “ROCK1 and ROCK2 were significantly upregulated in BPH tissues… Y-27632… inhibited cell proliferation, fibrosis, epithelial–mesenchymal transition… ROCK downregulation inhibited the β-catenin signaling pathway… and TGF‑β/Smad2/3 signaling… reversed prostatic hyperplasia and fibrosis in BPH model rats” (Shan 2024) (shan2024y27632targetingrock1&2 pages 7-11). - “Aberrant activation of transforming growth factor β (TGF‑β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs)… inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation” (Li 2024) (li2024aberrantactivationof pages 1-3). - “P. gingivalis… infection… upregulated the expression of interleukin‑6 (IL‑6; 4.47‑fold), interleukin‑6 receptor‑α (IL‑6Rα; 5.74‑fold) and glycoprotein 130 (gp130; 4.47‑fold)… activates the Akt pathway… induces BPH” (Wang 2024) (fei2024integratingspatialtranscriptomics pages 15-15).
Limitations - Some quantitative effect sizes (e.g., exact percent changes for in vivo prostate index) are reported qualitatively in the retrieved excerpts; deeper extraction from full texts would refine numerical precision. Nevertheless, the directional findings and core mechanisms are consistently supported across independent 2024 studies. (shan2024y27632targetingrock1&2 pages 7-11, fei2024integratingspatialtranscriptomics pages 15-15).
Conclusion BPH progression in the transition zone reflects an interplay between hypoxia‑driven epithelial EMT and plasticity (BE5, FOS), stromal induction (IGF1/CXCL13), and TGF‑β/ROCK‑mediated fibrosis that recruits and differentiates MSCs, reinforced by inflammatory IL‑6→AKT signaling and oxidative stress. These insights nominate actionable targets—ROCK1/2, IGF1/IGF1R, IL‑6/IL‑6R/gp130, and mitochondrial ROS—with preclinical evidence for disease modification alongside standard symptomatic therapies. (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11, santos2024cellplasticityin pages 1-2)
References
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