Elucidation of Inflammatory-Fibrotic Microenvironment in Human Urethral Stricture Disease

Elucidation of Inflammatory-Fibrotic Microenvironment in Human Urethral Stricture Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Elucidation of Inflammatory-Fibrotic Microenvironment in Human Urethral Stricture Disease Varshiny Gopinath, Manesh Kumar Panner Selvam, Jill Buckley, Jennifer Anger, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9307477/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 12 You are reading this latest preprint version Abstract (248 words) Background: Urethral stricture disease (USD) is marked by inflammation with subsequent tissue fibrosis that disrupts urinary flow. Recent studies suggest lower urinary tract biome dysbiosis increases proinflammatory cytokines, impeding tissue repair as well as promoting fibrotic scarring of the urethra. Despite these insights, the comprehensive molecular mechanisms underlying the formation, progression, and recurrence of the USD remain unclear. We aim to identify novel molecular targets and designate pathways contributing to USD, thereby identifying potential targets for future therapeutic interventions. Methods: We performed a comprehensive multi-modal analysis in USD patient urine and scar tissues. Urinary cytokines were assayed, transcriptome profiling and pathway enrichment were performed, and network mapping identified fibrotic hubs. Biomechanical tissue stiffness was quantified by atomic force microscopy (AFM), and protein and histological validation employed both immunostaining and Western blotting. Results: IL-1β, IL-6, IL-8, TNF-β, IL-10 were significantly elevated in USD. Transcriptomic profiling revealed 745 differentially expressed genes, with enrichment in ECM organization, cytokine storm, TGF-β, integrin, IL-17A, WNT/β-catenin. ECM organization and cytokine storm are identified as central interactive hubs, dominated by collagen and fibrogenic regulators such as SMAD3 and TGF-β1. Tissue stiffness increased threefold in USD tissues compared to controls, highlighting ECM remodeling. Immunostaining demonstrated enhanced vimentin, elastin, COL1, and TGF-β expression, along with Western blot studies validating elevated protein levels. Conclusion: The integrative approach evaluating pathway enrichment with transcriptome profiling reveals novel interconnections between mechanisms of inflammation, matrix remodeling, and mechanotransduction driving USD. The findings provide a mechanistic foundation for individualized models and therapeutic targets. Graphical abstract Health sciences/Biomarkers Biological sciences/Cell biology Biological sciences/Computational biology and bioinformatics Health sciences/Diseases Health sciences/Medical research Biological sciences/Molecular biology Urethral stricture disease fibrosis ECM remodeling and inflammation. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction USD affects approximately 0.6% of men and accounts 1.5 million office visits annually in the United States alone 1 . USD is characterized by progressive fibrotic narrowing of the urethral lumen, resulting in incomplete emptying and recurrent urinary tract infections that substantially impair quality of life 2 , 3 . Despite advances in surgical techniques, including urethroplasty recurrence rates remain significant 4 . USD pathophysiology has been attributed to inflammatory conditions from trauma, infection, or idiopathic causes that trigger aberrant wound healing 5 . However, precise molecular mechanisms driving the transition from acute injury to chronic fibrotic remodeling remain poorly defined. While prior studies have described inflammatory cell infiltration, myofibroblast activation, and excessive extracellular matrix deposition, a comprehensive, multi-dimensional analysis integrating inflammatory, transcriptomic, and biomechanical perspectives is lacking. Furthermore, the interplay between systemic and local inflammatory markers, tissue-level transcriptomic alterations, and resultant biomechanical changes have not been systematically investigated. Tissue stiffening, which compromises urethral compliance and underlies obstructive symptoms, is a hallmark of fibrotic disease. Mechanotransduction pathways, wherein ECM stiffening induces fibroblast-to-myofibroblast differentiation through integrin-mediated signaling and cytoskeletal reorganization, are well-established in cardiac and pulmonary fibrosis 6 , 7 . Identification of urinary biomarkers reflecting these pathological processes could provide non-invasive tools for disease monitoring and treatment stratification 8 . Chronic inflammation, dysregulated matrix remodeling driven by transforming growth factor-beta (TGF-β) signaling, and altered tissue mechanics synergistically promote fibrogenesis 9 . In hepatic and pulmonary fibrosis, TGF-β induces expression of collagen types I and III, fibronectin, and protease inhibitors, amplifying scar formation 10 , 11 . Whether similar regulatory mechanisms operate in USD remains unexplored, representing a major barrier to the therapeutic development of and predictive biomarkers for disease progression and treatment response 12 – 14 . Understanding these multi-scale relationships is critical for identifying which specific molecular alterations translate into clinically relevant mechanical dysfunction. The current management of USD is hindered by three critical limitations: limited understanding of the molecular mechanisms driving fibrotic progression, a lack of disease severity predictive biomarkers for recurrence, and a lack of targeted therapeutic strategies that address the underlying pathophysiology rather than managing mechanical obstruction 15 . To address the gaps in USD pathogenesis, we aim to provide a comprehensive, multi-dimensional characterization by integrating inflammatory, transcriptomic, and biomechanical analyses. We hypothesize USD involves coordinated activation of pro-fibrotic signaling networks encompassing inflammatory, matrix remodeling, and mechanotransduction pathways that converge to drive pathological tissue stiffening and clinical disease manifestation, analogous to mechanisms observed in systemic fibrotic disorders. We have characterized urinary inflammatory cytokines to identify potential non-invasive biomarkers of disease progression, performed genome-wide tissue transcriptomic analyses to define differentially expressed genes and molecular signatures of fibrosis, quantified tissue stiffness to establish the biomechanical dimension of pathology, and validated key molecular markers at the protein level to confirm the functional translation of transcriptomic alterations. 2. Materials and Methods Detailed materials and reagents are included in the supplementary section. Methods Detailed explanations of protocols are included in the supplementary section of the manuscript. 2.1 Patient Recruitment and Sample Collection Urethral scar tissues were obtained from USD patients undergoing urethroplasty, and control tissues were obtained from patients during gender-affirming vaginoplasty. Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Board (IRB) of the University of California San Diego (UCSD) ( https://irb.ucsd.edu/ ) under protocol number 190443. We confirm that all methods were performed in accordance with the relevant guidelines and regulations. 2.2 Multiplex Cytokine Analysis in Urine Samples Urinary cytokine levels were quantified using the V-PLEX Proinflammatory Panel, a multiplexed electrochemiluminescence-based immunoassay capable of simultaneously measuring 10 inflammatory cytokines. The samples were analyzed as per the MSD kit protocol. 2.3 Gene Transcriptomic Analysis Total RNA was isolated and purified, then quantified via Nanodrop spectrophotometer. Complementary DNA library preparation and bulk RNA-seq were conducted at the UCSD IGM Genomics core using Illumina technology. Data processing and analysis utilized BioJupies and R scripts. For the Bioinformatic analysis, an initial Core Analysis was performed, followed by Functional Analysis to identify fibrosis-associated canonical pathways and key molecular interaction networks. 2.4 Biophysical Characterization of Tissue Stiffness Using Atomic Force Microscopy (AFM nanoindentation) Fresh-frozen urethral tissue samples (USD and control) were sliced and mounted onto 10 mm glass coverslips. AFM cantilevers with known spring constants were calibrated using the standard thermal noise method and used for imaging tissue sections in PBS buffer at room temperature using a fluid cell. Nanoindentation measurements were performed after imaging by making multiple indentations (typically 10–20 per sample) across different regions at a constant tip displacement rate and depth. Force-distance curves were recorded and analyzed for quantitative measurements expressed in terms of stiffness, and comparative analysis was performed between the USD and control groups. Representative AFM images of tissue surface topography were acquired, showing ECM fiber organization and architecture. 2.5 Statistical Analysis Statistical significance was determined using GraphPad Prism software And one-way ANOVA was performed to evaluate significance among the groups. 3. Results 3.1 Urinary cytokine evaluation This analysis revealed that 5 out of 10 inflammation-related cytokines (IL1-β, IL-6, IL-8, TNF-β) were significantly elevated in USD patients (Fig. 1). IL-8 was considerably higher. Increased IL-6 levels correlated with strictures diagnosed over 5 years ago. IL-8, IL-10, and TNF-β showed a significant correlation with a history of prior transurethral interventions. Patients who underwent multiple procedures had lower IL-10 and TNF-β, while patients who had not received any intervention had significantly lower values of IL-8. 3.2 Gene transcriptomic analysis This analysis identified 745 differentially expressed genes from a total of 26,975 analyzed, indicating substantial transcriptomic changes between control and stricture urethral tissues. Of these, 487 genes were overexpressed, and 258 were underexpressed in USD tissue, as shown in the volcano plots (Fig. 2b). 3.3 Gene markers expression and gene ontology classification analysis The expression analysis revealed that several fibrosis-associated genes—LAMA, NLRP3, COL1A1, COL1A2, MMP1, MMP2, MMP3, CXCL5, TLR9, and LOX—were upregulated in USD tissue compared to control. These genes are linked to increased extracellular matrix production (COL1A1, COL1A2, LOX), remodeling (MMP1, MMP2, MMP3), immune and inflammatory activation (CXCL5, TLR9, NLRP3), and cell adhesion (LAMA). The elevated expression of these markers indicates enhanced fibrogenesis and a tissue environment primed for fibrosis (Fig. 3). Gene ontology enrichment analysis revealed that the most significantly enriched biological processes in USD were extracellular matrix organization, collagen fibril formation, wound healing, and regulation of cell adhesion. Cellular component enrichment was dominated by genes associated with extracellular matrix, contractile fibers, and basement membrane. The findings signify the activation of key fibrotic pathways involving matrix deposition, adhesive interactions, and tissue remodeling in USD tissue compared to controls (Fig. SF1). 3.4 Gene pathway enrichment analysis The analysis revealed a marked increase in gene expression associated with cytokine storm signaling, integrin signaling, extracellular matrix organization, regulation of epithelial-mesenchymal transition (EMT), WNT/β-catenin, and TGF-β pathways—each of which is closely linked to fibrosis progression. Specifically, USD tissue showed a higher proportion of overexpressed genes within these pathways, including 199 for cytokine storm signaling, 122 for integrin signaling, 73 for ECM organization, 102 for EMT regulation, 82 for WNT/β-catenin, and 47 for TGF-β signaling. These transcriptomic changes indicate robust activation of inflammatory, matrix remodeling, and pro-fibrotic signaling (Fig. SF2). 3.5 Gene Interaction Enrichment Analysis Identifies Key Molecular Networks in Fibrosis To identify the biological processes underlying fibrosis development, we performed pathway enrichment analysis on differentially expressed genes. Seven major signaling pathways were significantly enriched, linked to extracellular matrix remodeling and inflammatory responses (Fig. 4). The ECM organization pathway as the central node in the network, with 28 differentially expressed genes, including multiple collagen isoforms (COL1A1, COL1A2, COL3A1, COL4A4, COL5A2, COL6A3, COL8A1, COL11A1, COL13A1), laminin subunits (LAMA2, LAMB3, LAMC2), and ECM-associated proteins (ADAM12, SERPINE1). The Cytokine Storm Signaling Pathway, characterized by upregulation of chemokines (CCL3, CCL11, CCL24, CXCL8, CXCL14, CXCL16), pattern recognition receptors (TLR7, TLR8, TLR9), and multiple HLA class II molecules (HLA-DMA, HLA-DRA, HLA-DOA, HLA-DPA1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DPB1), along with complement component C3 and interferon regulatory factor 1 (IRF1). TGF-β Signaling showed enrichment of canonical pro-fibrotic genes including CXCL3, COL4A4, and SERPINE1, with direct connections to ECM Organization. IL-17A Signaling in Fibroblasts featured upregulation of matrix metalloproteinases (MMP1, MMP3, MMP8), inflammatory mediators (CXCL5, IL-1β, LIF), collagen genes (COL1A1, COL1A2, COL8A1), and lysyl oxidase (LOX), demonstrating connectivity to both inflammatory and matrix hubs. Integrin Signaling was enriched with multiple integrin subunits (ITGAX, ITGA2, ITGB2), downstream effectors (ARPC1B, TNK2), and cytoskeletal proteins (MYL2, ACTN2), bridging TGF-β and ECM Organization pathways. WNT/β-catenin Signaling demonstrated upregulation of WNT ligands (WNT2, WNT4, WNT7B) with direct relation to EMT Regulation. The EMT Regulation pathway included fibroblast growth factors (FGFR4, FGF5), MMP2, MMP3, LOX, and thy-1 cell surface antigen (THY1). Network analysis revealed extensive crosstalk among all seven pathways, with ECM Organization and Cytokine Storm Signaling serving as primary convergence hubs connected predominantly by positive regulatory relationships (Fig. 4). The fibrosis-enhanced pathway analysis highlights the pro-fibrotic pathways (such as TGF-β1/SMAD3) driving fibroblast accumulation and ECM synthesis, while NR3C1, SIRT6, TERT, and mechanotransduction pathways like ROCK1 function to restrain the fibrotic response by targeting key molecular and biomechanical checkpoints (Fig. 4). 3.5 Biophysical characterization for fibrotic stiffness by AFM This analysis demonstrated that USD tissues exhibited markedly increased stiffness compared to control tissues. Quantitative measurements revealed that USD tissue stiffness was approximately threefold higher, correlating with notable accumulation of collagen fibers, as shown in AFM images marked with large deposition of thick ECM fibers (Fig. 5b). The elevated stiffness is indicative of fibrotic tissue remodeling. To elucidate the molecular mechanisms underlying this fibrotic phenotype, we performed pathway analysis focusing on mechanotransduction signaling. Network analysis identified five key hub genes with predicted activation states and strong interaction networks, shown in Table 1. PIEZO1, a mechanosensitive ion channel, demonstrated the highest activation z-score and directly responds to the increased mechanical stress imposed by stiffened tissue microenvironment. RHOA, a central regulator of actin cytoskeletal dynamics, was also significantly activated and showed robust interactions with multiple downstream effectors, including MMP1, MMP9, and key collagen genes (COL1A1, COL3A1, COL10A1), implicating RhoA in mechanically-driven ECM remodeling. PTK2 (FAK), a mechanically responsive kinase, exhibited extensive interactions with collagen isoforms and ECM-degrading proteases (MMP2, MMP9), linking focal adhesion signaling to collagen metabolism. YAP1, a mechanosensitive transcription regulator, displayed multiple interactions with fibrotic genes including COL1A1, COL3A1, and COL11A1, suggesting Hippo-YAP pathway involvement in mechanically-induced fibrotic gene expression. Table 1: Key genes associated with the mechano-transduction Pathway in USD pathogenesis 3.6 Extracellular matrix and fibrogenic markers staining This analysis demonstrated increased expression of vimentin, elastin, collagen type I (COL1), and TGF-β, consistent with previous findings that highlight their critical roles in fibrosis development. Irregular elastin fibers were observed both in immunostaining (Fig. 6b) and Verhoeff staining (Fig. 6h). Enhanced intra- and extracellular collagen deposition was evident in immunostaining (Fig. 6d) as well as Sirius Red staining (Fig. 6i). Additionally, upregulated TGF-β expression (Fig. 6d) was detected alongside co-expression of other fibrotic components, further supporting their contribution to fibrosis pathology. Western blot analysis showed higher non-significant expression levels of TGF-β and COL1A1 in the USD samples shown in the supplementary (Fig. SF3). 4. Discussion USD remains a significant clinical often resulting in debilitating urinary symptoms and morbidity with a high recurrence 16 – 19 . To the best of our knowledge, our study provides a first comprehensive investigation into the molecular, cellular, and biomechanical alterations underlying USD, emphasizing key pathways and markers implicated in fibrosis 13 . Our cytokine profiling of urine revealed significant elevation of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-β, alongside the anti-inflammatory cytokine IL-10, consistent with prior studies that implicate immune dysregulation in USD pathogenesis 8 , 20 , 21 . Particularly, the substantial increase in IL-8 and the association of IL-6 with chronic strictures highlight persistent inflammatory activity contributing to fibrotic progression, as observed in renal scar 22 . The pathway enrichment analysis revealed fibrosis orchestrated by a highly interconnected network of seven major signaling pathways that converge on extracellular matrix accumulation and inflammatory perpetuation. The central positioning of ECM organization as the primary network hub demonstrates that diverse pro-fibrotic signals, such as inflammatory 14 , mechanical 23 , and cellular pathways. The significant upregulation of multiple collagen isoforms, particularly fibrillar collagens (COL1A1, COL1A2, COL3A1) alongside basement membrane components (COL4A4, laminins), indicates comprehensive matrix remodeling, while the downregulation of COL17A1 suggests disrupted epithelial-stromal interactions may contribute to barrier dysfunction. The identification of cytokine storm signaling as a co-dominant hub highlights the critical role of sustained inflammation in driving pathological matrix deposition, with broad upregulation of chemokines, pattern recognition receptors, and HLA class II molecules indicating active recruitment of diverse immune cell populations and ongoing antigen presentation, which may contribute to disease recurrence. The extensive connectivity between cytokine storm and ECM organization pathways provides additional molecular evidence for the inflammatory-fibrotic crosstalk observed clinically, where inflammation drives matrix deposition and accumulated matrix further activates inflammatory cells, which was also evidenced in other fibrogenic diseases 24 . The enrichment of TGF-β signaling confirms its role as a vital regulator of USD fibrogenesis, highlighting its function as a key transducer of pro-fibrotic stimuli 25 . The expression of SERPINE1 (PAI-1) indicates active suppression of matrix degradation, suggesting fibrosis results from both increased synthesis and decreased turnover 26 . The enrichment of IL-17A signaling represents a distinct inflammatory-fibrotic axis, with the simultaneous upregulation of matrix metalloproteinases (MMPs) and collagens reflecting matrix remodeling. It also highlights the critical role of biomechanical forces in fibrosis, with integrins serving as bidirectional transducers that transmit mechanical information from stiff ECM to intracellular signaling 30 . Our analysis suggests ECM organization represents such a common effector, and strategies targeting matrix cross-linking (lysyl oxidase (LOX) inhibition), matrix stiffness (mechanotransduction inhibitors), or enhancing matrix degradation MMP activation or SERPINE1 inhibition) might interrupt the balance related to wound healing and result in fibrosis. Mechanobiological regulation via ROCK1 is also implicated, linking cellular contractility and matrix remodeling to fibrotic progression. Hence, the transcriptomic analysis corroborated the inflammatory and fibrotic signatures, identifying 745 differentially expressed genes between USD and control urethral tissues driving fibrosis in USD.​ The biomechanical characterization using AFM demonstrated approximately threefold increased tissue stiffness in USD specimens, directly validating the functional downstream of molecular changes. This mechanical stiffening, driven by collagen accumulation and crosslinking, likely perpetuates fibrosis through mechanotransduction feedback loops, as demonstrated by studies showing that substrate stiffness alone can activate fibroblast-to-myofibroblast differentiation 23 , 29 , 30 . The correlation between transcriptomic markers and biophysical properties establishes USD as a disease of pathological mechanobiology. The integrated activation of the mechanotransduction hub—comprising PIEZO1, RHOA, PTK2, and YAP1—demonstrates that mechanical stiffness could act as a disease driver rather than merely a consequence of fibrotic remodeling. The extensive interaction networks among mechanotransduction hubs and their downstream effectors—collagen isoforms, MMPs, and inflammatory mediators—indicate that simple inhibition of individual targets may prove insufficient for therapeutic intervention. and highlights the need for multi-targeted strategies that simultaneously address mechanosensing pathways and mechanical properties of the tissue itself, potentially offering more effective disease modification. Immunohistochemical validation confirmed increased expression of vimentin, elastin, COL1, and TGF-β, with irregular elastin fiber architecture and enhanced collagen deposition. These findings corroborate the transcriptomic data and demonstrate the protein-level outcome of gene changes. The visualization of disorganized elastin fibers alongside excessive collagen deposition illustrates the architectural disruption characterizing fibrotic remodeling in USD. By elucidating these integrated molecular mechanisms, we have identified a panel of novel biomarkers—including the urinary cytokine signature, and ECM-associated proteins (collagen isoforms, laminins, vimentin, elastin)—that collectively serve as molecular indicators for USD diagnosis, severity stratification, and progression risk. These biomarkers, which were not previously characterized in USD, represent the first comprehensive molecular signature capable of distinguishing USD from normal urethral tissue and enabling non-invasive patient stratification through easily accessible urinary sampling. Overall, our research provides the first comprehensive analysis comprising the pathophysiology of USD. The identification of specific molecular signatures and pathway interactions offers mechanistic insights with potential translational implications. This study establishes a foundation for the development of patient-specific disease models that incorporate the severity of urethral stricture, enabling tailored treatment strategies through emerging technologies such as patient-derived stricture organoids. 5. Conclusion In summary, the multi-modal analyses elucidates the complex interplay of inflammatory, fibrotic, and mechanical factors driving USD pathogenesis. Elevated cytokines and persistent inflammatory signaling likely prime the tissue niche for fibrotic transformation, reinforced by dysregulated gene expression driving ECM remodeling and cellular adhesion. Increased matrix stiffness not only reflects structural tissue changes but likely acts as a positive feedback mechanism, enhancing fibroblast activation. These insights underscore novel potential targets for therapeutic intervention aimed at modulating inflammation, ECM dynamics, and mechanotransduction to mitigate urethral fibrosis and improve clinical outcomes. Declarations Conflict of interest Authors declare no known competing financial interests or personal relationships to influence the work reported in this paper. Author Contribution All authors were involved in the conceptualization of this project. V.G., M.K.P.S., and N.P. were involved in data curation. V.G., M.K.P.S., N.P., M.W., and M.R. participated in the formal analysis of the data. Experimental validation was performed by V.G. The original draft was written by V.G. Investigation was led by J.B. and M.R. Resources were provided by J.B. and M.R. Supervision was provided by J.A., K.S., M.R. All authors reviewed the manuscript. K.S., R.L., and M.R. provided funding for the project. Acknowledgments The authors acknowledge all sources of funding support. UCSD Academic Senate award (RG114357) and partial support by VA Merit award (5I01CX002401-03). We thank the IGM Core Facility at UCSD for gene sequencing and Mr. Jad Shahan for helping us with experiments. We also thank Nidhish Balakrishnan for helping with gene profiling studies. Data Availability The authors declare that all the required data supporting the findings of this study are available in the main article and the supplementary. We have updated the data availability statement to include a directly accessible link to the corresponding dataset for review. The reviewer’s link is enclosed: https://dataview.ncbi.nlm.nih.gov/object/PRJNA1451906?reviewer=rhftjtvfkohsmeaqevhgaq78jq “The sequencing data have been deposited in the NCBI BioSample database under accession numbers SAMN57202786–SAMN57202791.” Accession Sample Name SPUID Organism Tax ID Isolate SAMN57202786 Control-1 Control-1 Homo sapiens 9606 NA SAMN57202787 Control-2 Control-2 Homo sapiens 9606 NA SAMN57202788 Control-3 Control-3 Homo sapiens 9606 NA SAMN57202789 Stricture-1 Stricture-1 Homo sapiens 9606 NA SAMN57202790 Stricture-2 Stricture-2 Homo sapiens 9606 NA SAMN57202791 Stricture-3 Stricture-3 Homo sapiens 9606 NA https://www.ncbi.nlm.nih.gov/biosample/57202786 https://www.ncbi.nlm.nih.gov/biosample/57202787 https://www.ncbi.nlm.nih.gov/biosample/57202788 https://www.ncbi.nlm.nih.gov/biosample/57202789 https://www.ncbi.nlm.nih.gov/biosample/57202790 https://www.ncbi.nlm.nih.gov/biosample/57202791 References Santucci, R. A., Joyce, G. F. & Wise, M. 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Supplementary Files GA.jpeg Graphical abstract Supplementary.docx SupplementaryR2.pdf Supplementaryfile.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 11 May, 2026 Reviews received at journal 08 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers agreed at journal 03 May, 2026 Reviews received at journal 28 Apr, 2026 Reviewers agreed at journal 28 Apr, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 21 Apr, 2026 Editor assigned by journal 21 Apr, 2026 Editor invited by journal 21 Apr, 2026 Submission checks completed at journal 16 Apr, 2026 First submitted to journal 16 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9307477","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":631296843,"identity":"f7737fe2-723a-4c26-9d39-414a017043b1","order_by":0,"name":"Varshiny Gopinath","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Varshiny","middleName":"","lastName":"Gopinath","suffix":""},{"id":631296844,"identity":"847e0aa2-cb62-456c-8160-30f97c01520e","order_by":1,"name":"Manesh Kumar Panner Selvam","email":"","orcid":"","institution":"Tulane University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Manesh","middleName":"Kumar Panner","lastName":"Selvam","suffix":""},{"id":631296845,"identity":"ccdca409-016e-4450-8f0b-f854ebb957ca","order_by":2,"name":"Jill Buckley","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Jill","middleName":"","lastName":"Buckley","suffix":""},{"id":631296846,"identity":"0a3867d2-f2a0-4ee5-84c4-b48a1962d7ad","order_by":3,"name":"Jennifer Anger","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Anger","suffix":""},{"id":631296847,"identity":"fde1e39c-cf87-4aad-b732-1c54270e1950","order_by":4,"name":"Kyoko Sakamoto","email":"","orcid":"","institution":"VA San Diego Healthcare System","correspondingAuthor":false,"prefix":"","firstName":"Kyoko","middleName":"","lastName":"Sakamoto","suffix":""},{"id":631296848,"identity":"73561535-0112-4036-a910-f635457b3343","order_by":5,"name":"Nirav Patel","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Nirav","middleName":"","lastName":"Patel","suffix":""},{"id":631296850,"identity":"329442bc-ceff-48ae-b497-3f91f10fdbc1","order_by":6,"name":"Ratnesh Lal","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Ratnesh","middleName":"","lastName":"Lal","suffix":""},{"id":631296852,"identity":"4c1ab53d-cb22-4d16-8de1-f2f6cd2f2207","order_by":7,"name":"Michael Witthaus","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Witthaus","suffix":""},{"id":631296854,"identity":"6114da80-0ebb-4f2c-9e84-b9872c142d36","order_by":8,"name":"Mahadevan Rajasekaran","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABIklEQVRIie2RMUsDMRSAcwRyS1rXk6PcLxASAlHhWv+Kx8FNLRSETlICQrajs1T8Dy7FMRLoFDo7HghON+giCgc1lutkTjo65IPA4+V9vJcXADyefwppDwDvAoA+wLs4EPvsX0pwa8sQOkDZawD2DlFOlrqafjYpO1rq15fhY5qgpFQQX88HIrxZRQ6FbwpCS1nwaFOcsokpqET9S4jXmgm8njkVAwjpCZ0CA3g8kTqQCBM7ocpENOZuJXyjTbNNExN+xOdye9Eq80wkdYeCCcNIcWIwjwOpslaBtgvuUqZsIHNGDZ4dlzLPJRqTpzv7FomLqzP3YCtaNyN6b4PoS46GC2hoVduNLUL98Ozasv2I39tXu7y7/AdYdd95PB6Px/INZD9dVuBqI6YAAAAASUVORK5CYII=","orcid":"","institution":"VA San Diego Healthcare System","correspondingAuthor":true,"prefix":"","firstName":"Mahadevan","middleName":"","lastName":"Rajasekaran","suffix":""}],"badges":[],"createdAt":"2026-04-03 00:53:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9307477/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9307477/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108492959,"identity":"fb8b9e74-5f1c-4f68-891a-5b03c0f815fe","added_by":"auto","created_at":"2026-05-05 09:59:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92554,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eInflammatory cytokine analysis in the urine sample of non-stricture (control) and USD patients.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/9f669444d8a40c7af6ee7a80.jpg"},{"id":108385645,"identity":"e90f5e83-eb1b-44ea-bb20-4112fdff508d","added_by":"auto","created_at":"2026-05-04 06:04:34","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":147546,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eGene transcriptomic analysis. a) Flowchart representing total genes analyzed, differentially expressed genes (DEGs), and counts of upregulated and downregulated genes. Volcano plots showing DEGs based on p-value, b) fibrotic vs control\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/a76b11aae3a72e3224a3b9b4.jpeg"},{"id":109067661,"identity":"e68c97d0-2eff-4f02-bb75-f9d14fb0284b","added_by":"auto","created_at":"2026-05-12 09:59:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":116233,"visible":true,"origin":"","legend":"\u003cp\u003eFibrosis-associated gene expression and gene ontology enrichment in USD. Bar plot displaying log2 expression ratios for selected genes in USD versus control tissue. Key pro-fibrotic genes (e.g., LAMA2, NLRP3, LOX, COL1A2, COL1A1, MMP1/2/3, TLR9, CXCL5) are highlighted.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/888a0e70cfb3899782e8ecc8.png"},{"id":108492332,"identity":"ca39e0d8-9563-4142-b712-c56d04e837a6","added_by":"auto","created_at":"2026-05-05 09:57:30","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":464724,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular Interaction Network Maps (Left side shown network) Seven major pathways interactome regulating fibrosis. (Right side shown network) Fibrosis-enriched pathway. Nodes represent genes or proteins; arrows indicate molecular interactions (activation: orange, inhibition: blue); edge styles (dashed/solid) show predicted versus validated links. Nodes are colored or shaped to distinguish molecule types (e.g., ECM, signaling, transcription factors). Pathways and network hubs are labeled; thicker edges denote stronger or highly supported interactions.\u003c/p\u003e","description":"","filename":"4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/6a7f675a7b312263ee3cc380.jpeg"},{"id":108803799,"identity":"36eb6820-7f87-46fc-9005-c949594be495","added_by":"auto","created_at":"2026-05-08 15:07:31","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":228031,"visible":true,"origin":"","legend":"\u003cp\u003eAFM analysis of human tissue samples: (a) AFM image of control tissue, (b) AFM image of USD tissue, (c) Quantitative comparison of tissue stiffness between control and USD groups measured using the nanoindentation method. One-way ANOVA was performed to evaluate the significance among groups.\u003c/p\u003e","description":"","filename":"5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/2c21dc129bf3554bb61c203b.jpeg"},{"id":108385652,"identity":"ad46337c-031a-4fa3-a189-70390ba382d1","added_by":"auto","created_at":"2026-05-04 06:04:34","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":881387,"visible":true,"origin":"","legend":"\u003cp\u003eMicroscopic validation of fibrosis markers in tissue sections. Panels (a–d) show immunostaining images, while panels (e–j) present immunohistochemistry images of control and human USD tissues.\u003c/p\u003e","description":"","filename":"6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/2b38bb9304ad56acf1a963eb.jpeg"},{"id":109069275,"identity":"92ecc821-2e60-46f2-90d9-abc56c7f247e","added_by":"auto","created_at":"2026-05-12 10:22:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2205052,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/2426859c-9897-45fb-b6fa-0e3649e69ff6.pdf"},{"id":108385643,"identity":"9c313ba7-84c3-4d0d-95a9-9fbffe80fc06","added_by":"auto","created_at":"2026-05-04 06:04:34","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":125670,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical abstract\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"GA.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/c96b87cccd36ffc241884f9c.jpeg"},{"id":108385648,"identity":"32e5e72e-ce08-4547-8052-3d83f893729a","added_by":"auto","created_at":"2026-05-04 06:04:34","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":481577,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/6826f95b062c004723934e66.docx"},{"id":108385647,"identity":"212c9641-cde1-479f-8d15-3931f881d0eb","added_by":"auto","created_at":"2026-05-04 06:04:34","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":380922,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryR2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/695adc154e3d4abf722772c5.pdf"},{"id":108385649,"identity":"7afc17e6-7fef-4849-ae68-905263573b9c","added_by":"auto","created_at":"2026-05-04 06:04:34","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":13704,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-9307477/v1/440cc91dcaec9de040e72f6f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elucidation of Inflammatory-Fibrotic Microenvironment in Human Urethral Stricture Disease","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eUSD affects approximately 0.6% of men and accounts 1.5\u0026nbsp;million office visits annually in the United States alone\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. USD is characterized by progressive fibrotic narrowing of the urethral lumen, resulting in incomplete emptying and recurrent urinary tract infections that substantially impair quality of life\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Despite advances in surgical techniques, including urethroplasty recurrence rates remain significant\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. USD pathophysiology has been attributed to inflammatory conditions from trauma, infection, or idiopathic causes that trigger aberrant wound healing \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, precise molecular mechanisms driving the transition from acute injury to chronic fibrotic remodeling remain poorly defined. While prior studies have described inflammatory cell infiltration, myofibroblast activation, and excessive extracellular matrix deposition, a comprehensive, multi-dimensional analysis integrating inflammatory, transcriptomic, and biomechanical perspectives is lacking. Furthermore, the interplay between systemic and local inflammatory markers, tissue-level transcriptomic alterations, and resultant biomechanical changes have not been systematically investigated.\u003c/p\u003e \u003cp\u003eTissue stiffening, which compromises urethral compliance and underlies obstructive symptoms, is a hallmark of fibrotic disease. Mechanotransduction pathways, wherein ECM stiffening induces fibroblast-to-myofibroblast differentiation through integrin-mediated signaling and cytoskeletal reorganization, are well-established in cardiac and pulmonary fibrosis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Identification of urinary biomarkers reflecting these pathological processes could provide non-invasive tools for disease monitoring and treatment stratification\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Chronic inflammation, dysregulated matrix remodeling driven by transforming growth factor-beta (TGF-β) signaling, and altered tissue mechanics synergistically promote fibrogenesis\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In hepatic and pulmonary fibrosis, TGF-β induces expression of collagen types I and III, fibronectin, and protease inhibitors, amplifying scar formation\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Whether similar regulatory mechanisms operate in USD remains unexplored, representing a major barrier to the therapeutic development of and predictive biomarkers for disease progression and treatment response\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUnderstanding these multi-scale relationships is critical for identifying which specific molecular alterations translate into clinically relevant mechanical dysfunction. The current management of USD is hindered by three critical limitations: limited understanding of the molecular mechanisms driving fibrotic progression, a lack of disease severity predictive biomarkers for recurrence, and a lack of targeted therapeutic strategies that address the underlying pathophysiology rather than managing mechanical obstruction\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo address the gaps in USD pathogenesis, we aim to provide a comprehensive, multi-dimensional characterization by integrating inflammatory, transcriptomic, and biomechanical analyses. We hypothesize USD involves coordinated activation of pro-fibrotic signaling networks encompassing inflammatory, matrix remodeling, and mechanotransduction pathways that converge to drive pathological tissue stiffening and clinical disease manifestation, analogous to mechanisms observed in systemic fibrotic disorders. We have characterized urinary inflammatory cytokines to identify potential non-invasive biomarkers of disease progression, performed genome-wide tissue transcriptomic analyses to define differentially expressed genes and molecular signatures of fibrosis, quantified tissue stiffness to establish the biomechanical dimension of pathology, and validated key molecular markers at the protein level to confirm the functional translation of transcriptomic alterations.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eDetailed materials and reagents are included in the supplementary section.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e \u003c/p\u003e \u003cp\u003eDetailed explanations of protocols are included in the supplementary section of the manuscript.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patient Recruitment and Sample Collection\u003c/h2\u003e \u003cp\u003eUrethral scar tissues were obtained from USD patients undergoing urethroplasty, and control tissues were obtained from patients during gender-affirming vaginoplasty. Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Board (IRB) of the University of California San Diego (UCSD) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://irb.ucsd.edu/\u003c/span\u003e\u003cspan address=\"https://irb.ucsd.edu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) under protocol number 190443. We confirm that all methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Multiplex Cytokine Analysis in Urine Samples\u003c/h2\u003e \u003cp\u003eUrinary cytokine levels were quantified using the V-PLEX Proinflammatory Panel, a multiplexed electrochemiluminescence-based immunoassay capable of simultaneously measuring 10 inflammatory cytokines. The samples were analyzed as per the MSD kit protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Gene Transcriptomic Analysis\u003c/h2\u003e \u003cp\u003eTotal RNA was isolated and purified, then quantified via Nanodrop spectrophotometer. Complementary DNA library preparation and bulk RNA-seq were conducted at the UCSD IGM Genomics core using Illumina technology. Data processing and analysis utilized BioJupies and R scripts. For the Bioinformatic analysis, an initial Core Analysis was performed, followed by Functional Analysis to identify fibrosis-associated canonical pathways and key molecular interaction networks.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Biophysical Characterization of Tissue Stiffness Using Atomic Force Microscopy (AFM nanoindentation)\u003c/h2\u003e \u003cp\u003eFresh-frozen urethral tissue samples (USD and control) were sliced and mounted onto 10 mm glass coverslips. AFM cantilevers with known spring constants were calibrated using the standard thermal noise method and used for imaging tissue sections in PBS buffer at room temperature using a fluid cell. Nanoindentation measurements were performed after imaging by making multiple indentations (typically 10\u0026ndash;20 per sample) across different regions at a constant tip displacement rate and depth. Force-distance curves were recorded and analyzed for quantitative measurements expressed in terms of stiffness, and comparative analysis was performed between the USD and control groups. Representative AFM images of tissue surface topography were acquired, showing ECM fiber organization and architecture.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical significance was determined using GraphPad Prism software And one-way ANOVA was performed to evaluate significance among the groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003e3.1 Urinary cytokine evaluation\u003c/h2\u003e\n \u003cdiv\u003e\n \u003cp\u003eThis analysis revealed that 5 out of 10 inflammation-related cytokines (IL1-\u0026beta;, IL-6, IL-8, TNF-\u0026beta;) were significantly elevated in USD patients (Fig.\u0026nbsp;1). IL-8 was considerably higher. Increased IL-6 levels correlated with strictures diagnosed over 5 years ago. IL-8, IL-10, and TNF-\u0026beta; showed a significant correlation with a history of prior transurethral interventions. Patients who underwent multiple procedures had lower IL-10 and TNF-\u0026beta;, while patients who had not received any intervention had significantly lower values of IL-8.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003e3.2 Gene transcriptomic analysis\u003c/h2\u003e\n \u003cp\u003eThis analysis identified 745 differentially expressed genes from a total of 26,975 analyzed, indicating substantial transcriptomic changes between control and stricture urethral tissues. Of these, 487 genes were overexpressed, and 258 were underexpressed in USD tissue, as shown in the volcano plots (Fig.\u0026nbsp;2b).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003e3.3 Gene markers expression and gene ontology classification analysis\u003c/h2\u003e\n \u003cp\u003eThe expression analysis revealed that several fibrosis-associated genes\u0026mdash;LAMA, NLRP3, COL1A1, COL1A2, MMP1, MMP2, MMP3, CXCL5, TLR9, and LOX\u0026mdash;were upregulated in USD tissue compared to control. These genes are linked to increased extracellular matrix production (COL1A1, COL1A2, LOX), remodeling (MMP1, MMP2, MMP3), immune and inflammatory activation (CXCL5, TLR9, NLRP3), and cell adhesion (LAMA). The elevated expression of these markers indicates enhanced fibrogenesis and a tissue environment primed for fibrosis (Fig.\u0026nbsp;3). Gene ontology enrichment analysis revealed that the most significantly enriched biological processes in USD were extracellular matrix organization, collagen fibril formation, wound healing, and regulation of cell adhesion. Cellular component enrichment was dominated by genes associated with extracellular matrix, contractile fibers, and basement membrane. The findings signify the activation of key fibrotic pathways involving matrix deposition, adhesive interactions, and tissue remodeling in USD tissue compared to controls (Fig. SF1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003e3.4 Gene pathway enrichment analysis\u003c/h2\u003e\n \u003cp\u003eThe analysis revealed a marked increase in gene expression associated with cytokine storm signaling, integrin signaling, extracellular matrix organization, regulation of epithelial-mesenchymal transition (EMT), WNT/\u0026beta;-catenin, and TGF-\u0026beta; pathways\u0026mdash;each of which is closely linked to fibrosis progression. Specifically, USD tissue showed a higher proportion of overexpressed genes within these pathways, including 199 for cytokine storm signaling, 122 for integrin signaling, 73 for ECM organization, 102 for EMT regulation, 82 for WNT/\u0026beta;-catenin, and 47 for TGF-\u0026beta; signaling. These transcriptomic changes indicate robust activation of inflammatory, matrix remodeling, and pro-fibrotic signaling (Fig. SF2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003e3.5 Gene Interaction Enrichment Analysis Identifies Key Molecular Networks in Fibrosis\u003c/h2\u003e\n \u003cp\u003eTo identify the biological processes underlying fibrosis development, we performed pathway enrichment analysis on differentially expressed genes. Seven major signaling pathways were significantly enriched, linked to extracellular matrix remodeling and inflammatory responses (Fig.\u0026nbsp;4). The ECM organization pathway as the central node in the network, with 28 differentially expressed genes, including multiple collagen isoforms (COL1A1, COL1A2, COL3A1, COL4A4, COL5A2, COL6A3, COL8A1, COL11A1, COL13A1), laminin subunits (LAMA2, LAMB3, LAMC2), and ECM-associated proteins (ADAM12, SERPINE1). The Cytokine Storm Signaling Pathway, characterized by upregulation of chemokines (CCL3, CCL11, CCL24, CXCL8, CXCL14, CXCL16), pattern recognition receptors (TLR7, TLR8, TLR9), and multiple HLA class II molecules (HLA-DMA, HLA-DRA, HLA-DOA, HLA-DPA1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DPB1), along with complement component C3 and interferon regulatory factor 1 (IRF1). TGF-\u0026beta; Signaling showed enrichment of canonical pro-fibrotic genes including CXCL3, COL4A4, and SERPINE1, with direct connections to ECM Organization. IL-17A Signaling in Fibroblasts featured upregulation of matrix metalloproteinases (MMP1, MMP3, MMP8), inflammatory mediators (CXCL5, IL-1\u0026beta;, LIF), collagen genes (COL1A1, COL1A2, COL8A1), and lysyl oxidase (LOX), demonstrating connectivity to both inflammatory and matrix hubs. Integrin Signaling was enriched with multiple integrin subunits (ITGAX, ITGA2, ITGB2), downstream effectors (ARPC1B, TNK2), and cytoskeletal proteins (MYL2, ACTN2), bridging TGF-\u0026beta; and ECM Organization pathways. WNT/\u0026beta;-catenin Signaling demonstrated upregulation of WNT ligands (WNT2, WNT4, WNT7B) with direct relation to EMT Regulation. The EMT Regulation pathway included fibroblast growth factors (FGFR4, FGF5), MMP2, MMP3, LOX, and thy-1 cell surface antigen (THY1). Network analysis revealed extensive crosstalk among all seven pathways, with ECM Organization and Cytokine Storm Signaling serving as primary convergence hubs connected predominantly by positive regulatory relationships (Fig.\u0026nbsp;4). The fibrosis-enhanced pathway analysis highlights the pro-fibrotic pathways (such as TGF-\u0026beta;1/SMAD3) driving fibroblast accumulation and ECM synthesis, while NR3C1, SIRT6, TERT, and mechanotransduction pathways like ROCK1 function to restrain the fibrotic response by targeting key molecular and biomechanical checkpoints (Fig.\u0026nbsp;4).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003e3.5 Biophysical characterization for fibrotic stiffness by AFM\u003c/h2\u003e\n \u003cp\u003eThis analysis demonstrated that USD tissues exhibited markedly increased stiffness compared to control tissues. Quantitative measurements revealed that USD tissue stiffness was approximately threefold higher, correlating with notable accumulation of collagen fibers, as shown in AFM images marked with large deposition of thick ECM fibers (Fig.\u0026nbsp;5b). The elevated stiffness is indicative of fibrotic tissue remodeling. To elucidate the molecular mechanisms underlying this fibrotic phenotype, we performed pathway analysis focusing on mechanotransduction signaling. Network analysis identified five key hub genes with predicted activation states and strong interaction networks, shown in Table\u0026nbsp;1. PIEZO1, a mechanosensitive ion channel, demonstrated the highest activation z-score and directly responds to the increased mechanical stress imposed by stiffened tissue microenvironment. RHOA, a central regulator of actin cytoskeletal dynamics, was also significantly activated and showed robust interactions with multiple downstream effectors, including MMP1, MMP9, and key collagen genes (COL1A1, COL3A1, COL10A1), implicating RhoA in mechanically-driven ECM remodeling. PTK2 (FAK), a mechanically responsive kinase, exhibited extensive interactions with collagen isoforms and ECM-degrading proteases (MMP2, MMP9), linking focal adhesion signaling to collagen metabolism. YAP1, a mechanosensitive transcription regulator, displayed multiple interactions with fibrotic genes including COL1A1, COL3A1, and COL11A1, suggesting Hippo-YAP pathway involvement in mechanically-induced fibrotic gene expression.\u003c/p\u003e\n \u003cp\u003eTable 1: Key genes associated with the mechano-transduction Pathway in USD pathogenesis\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003e3.6 Extracellular matrix and fibrogenic markers staining\u003c/h2\u003e\n \u003cdiv\u003e\n \u003cp\u003eThis analysis demonstrated increased expression of vimentin, elastin, collagen type I (COL1), and TGF-\u0026beta;, consistent with previous findings that highlight their critical roles in fibrosis development. Irregular elastin fibers were observed both in immunostaining (Fig.\u0026nbsp;6b) and Verhoeff staining (Fig.\u0026nbsp;6h). Enhanced intra- and extracellular collagen deposition was evident in immunostaining (Fig.\u0026nbsp;6d) as well as Sirius Red staining (Fig.\u0026nbsp;6i). Additionally, upregulated TGF-\u0026beta; expression (Fig.\u0026nbsp;6d) was detected alongside co-expression of other fibrotic components, further supporting their contribution to fibrosis pathology. Western blot analysis showed higher non-significant expression levels of TGF-\u0026beta; and COL1A1 in the USD samples shown in the supplementary (Fig. SF3).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eUSD remains a significant clinical often resulting in debilitating urinary symptoms and morbidity with a high recurrence\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. To the best of our knowledge, our study provides a first comprehensive investigation into the molecular, cellular, and biomechanical alterations underlying USD, emphasizing key pathways and markers implicated in fibrosis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Our cytokine profiling of urine revealed significant elevation of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-β, alongside the anti-inflammatory cytokine IL-10, consistent with prior studies that implicate immune dysregulation in USD pathogenesis\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Particularly, the substantial increase in IL-8 and the association of IL-6 with chronic strictures highlight persistent inflammatory activity contributing to fibrotic progression, as observed in renal scar\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe pathway enrichment analysis revealed fibrosis orchestrated by a highly interconnected network of seven major signaling pathways that converge on extracellular matrix accumulation and inflammatory perpetuation. The central positioning of ECM organization as the primary network hub demonstrates that diverse pro-fibrotic signals, such as inflammatory\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, mechanical\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, and cellular pathways. The significant upregulation of multiple collagen isoforms, particularly fibrillar collagens (COL1A1, COL1A2, COL3A1) alongside basement membrane components (COL4A4, laminins), indicates comprehensive matrix remodeling, while the downregulation of COL17A1 suggests disrupted epithelial-stromal interactions may contribute to barrier dysfunction. The identification of cytokine storm signaling as a co-dominant hub highlights the critical role of sustained inflammation in driving pathological matrix deposition, with broad upregulation of chemokines, pattern recognition receptors, and HLA class II molecules indicating active recruitment of diverse immune cell populations and ongoing antigen presentation, which may contribute to disease recurrence. The extensive connectivity between cytokine storm and ECM organization pathways provides additional molecular evidence for the inflammatory-fibrotic crosstalk observed clinically, where inflammation drives matrix deposition and accumulated matrix further activates inflammatory cells, which was also evidenced in other fibrogenic diseases\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The enrichment of TGF-β signaling confirms its role as a vital regulator of USD fibrogenesis, highlighting its function as a key transducer of pro-fibrotic stimuli\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The expression of SERPINE1 (PAI-1) indicates active suppression of matrix degradation, suggesting fibrosis results from both increased synthesis and decreased turnover\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. The enrichment of IL-17A signaling represents a distinct inflammatory-fibrotic axis, with the simultaneous upregulation of matrix metalloproteinases (MMPs) and collagens reflecting matrix remodeling. It also highlights the critical role of biomechanical forces in fibrosis, with integrins serving as bidirectional transducers that transmit mechanical information from stiff ECM to intracellular signaling \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Our analysis suggests ECM organization represents such a common effector, and strategies targeting matrix cross-linking (lysyl oxidase (LOX) inhibition), matrix stiffness (mechanotransduction inhibitors), or enhancing matrix degradation MMP activation or SERPINE1 inhibition) might interrupt the balance related to wound healing and result in fibrosis. Mechanobiological regulation via ROCK1 is also implicated, linking cellular contractility and matrix remodeling to fibrotic progression. Hence, the transcriptomic analysis corroborated the inflammatory and fibrotic signatures, identifying 745 differentially expressed genes between USD and control urethral tissues driving fibrosis in USD.​\u003c/p\u003e \u003cp\u003eThe biomechanical characterization using AFM demonstrated approximately threefold increased tissue stiffness in USD specimens, directly validating the functional downstream of molecular changes. This mechanical stiffening, driven by collagen accumulation and crosslinking, likely perpetuates fibrosis through mechanotransduction feedback loops, as demonstrated by studies showing that substrate stiffness alone can activate fibroblast-to-myofibroblast differentiation\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. The correlation between transcriptomic markers and biophysical properties establishes USD as a disease of pathological mechanobiology. The integrated activation of the mechanotransduction hub\u0026mdash;comprising PIEZO1, RHOA, PTK2, and YAP1\u0026mdash;demonstrates that mechanical stiffness could act as a disease driver rather than merely a consequence of fibrotic remodeling.\u003c/p\u003e \u003cp\u003eThe extensive interaction networks among mechanotransduction hubs and their downstream effectors\u0026mdash;collagen isoforms, MMPs, and inflammatory mediators\u0026mdash;indicate that simple inhibition of individual targets may prove insufficient for therapeutic intervention. and highlights the need for multi-targeted strategies that simultaneously address mechanosensing pathways and mechanical properties of the tissue itself, potentially offering more effective disease modification.\u003c/p\u003e \u003cp\u003eImmunohistochemical validation confirmed increased expression of vimentin, elastin, COL1, and TGF-β, with irregular elastin fiber architecture and enhanced collagen deposition. These findings corroborate the transcriptomic data and demonstrate the protein-level outcome of gene changes. The visualization of disorganized elastin fibers alongside excessive collagen deposition illustrates the architectural disruption characterizing fibrotic remodeling in USD.\u003c/p\u003e \u003cp\u003eBy elucidating these integrated molecular mechanisms, we have identified a panel of novel biomarkers\u0026mdash;including the urinary cytokine signature, and ECM-associated proteins (collagen isoforms, laminins, vimentin, elastin)\u0026mdash;that collectively serve as molecular indicators for USD diagnosis, severity stratification, and progression risk. These biomarkers, which were not previously characterized in USD, represent the first comprehensive molecular signature capable of distinguishing USD from normal urethral tissue and enabling non-invasive patient stratification through easily accessible urinary sampling.\u003c/p\u003e \u003cp\u003eOverall, our research provides the first comprehensive analysis comprising the pathophysiology of USD. The identification of specific molecular signatures and pathway interactions offers mechanistic insights with potential translational implications. This study establishes a foundation for the development of patient-specific disease models that incorporate the severity of urethral stricture, enabling tailored treatment strategies through emerging technologies such as patient-derived stricture organoids.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn summary, the multi-modal analyses elucidates the complex interplay of inflammatory, fibrotic, and mechanical factors driving USD pathogenesis. Elevated cytokines and persistent inflammatory signaling likely prime the tissue niche for fibrotic transformation, reinforced by dysregulated gene expression driving ECM remodeling and cellular adhesion. Increased matrix stiffness not only reflects structural tissue changes but likely acts as a positive feedback mechanism, enhancing fibroblast activation. These insights underscore novel potential targets for therapeutic intervention aimed at modulating inflammation, ECM dynamics, and mechanotransduction to mitigate urethral fibrosis and improve clinical outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\n\u003ch2\u003eConflict of interest\u003c/h2\u003e\n\u003cp\u003eAuthors declare no known competing financial interests or personal relationships to influence the work reported in this paper.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eAll authors were involved in the conceptualization of this project. V.G., M.K.P.S., and N.P. were involved in data curation. V.G., M.K.P.S., N.P., M.W., and M.R. participated in the formal analysis of the data. Experimental validation was performed by V.G. The original draft was written by V.G. Investigation was led by J.B. and M.R. Resources were provided by J.B. and M.R. Supervision was provided by J.A., K.S., M.R. All authors reviewed the manuscript. K.S., R.L., and M.R. provided funding for the project.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors acknowledge all sources of funding support. UCSD Academic Senate award (RG114357) and partial support by VA Merit award (5I01CX002401-03). We thank the IGM Core Facility at UCSD for gene sequencing and Mr. Jad Shahan for helping us with experiments. We also thank Nidhish Balakrishnan for helping with gene profiling studies.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe authors declare that all the required data supporting the findings of this study are available in the main article and the supplementary. We have updated the data availability statement to include a directly accessible link to the corresponding dataset for review. The reviewer\u0026rsquo;s link is enclosed: https://dataview.ncbi.nlm.nih.gov/object/PRJNA1451906?reviewer=rhftjtvfkohsmeaqevhgaq78jq\u003c/p\u003e\n\u003cp\u003e\u0026ldquo;The sequencing data have been deposited in the NCBI BioSample database under accession numbers SAMN57202786\u0026ndash;SAMN57202791.\u0026rdquo;\u003c/p\u003e\n\u003cp\u003eAccession Sample Name SPUID Organism Tax ID Isolate \u003cbr /\u003e SAMN57202786 Control-1 Control-1 Homo sapiens 9606 NA \u003cbr /\u003e SAMN57202787 Control-2 Control-2 Homo sapiens 9606 NA \u003cbr /\u003e SAMN57202788 Control-3 Control-3 Homo sapiens 9606 NA \u003cbr /\u003e SAMN57202789 Stricture-1 Stricture-1 Homo sapiens 9606 NA \u003cbr /\u003e SAMN57202790 Stricture-2 Stricture-2 Homo sapiens 9606 NA \u003cbr /\u003e SAMN57202791 Stricture-3 Stricture-3 Homo sapiens 9606 NA\u003c/p\u003e\n\u003cp\u003e\u003cbr /\u003e https://www.ncbi.nlm.nih.gov/biosample/57202786\u003cbr /\u003e https://www.ncbi.nlm.nih.gov/biosample/57202787\u003cbr /\u003e https://www.ncbi.nlm.nih.gov/biosample/57202788\u003cbr /\u003e https://www.ncbi.nlm.nih.gov/biosample/57202789\u003cbr /\u003e https://www.ncbi.nlm.nih.gov/biosample/57202790\u003cbr /\u003e https://www.ncbi.nlm.nih.gov/biosample/57202791\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSantucci, R. 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Res.\u003c/em\u003e \u003cb\u003e95\u003c/b\u003e (3), 253\u0026ndash;260. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/01.RES.0000136520.07995.aa\u003c/span\u003e\u003cspan address=\"10.1161/01.RES.0000136520.07995.aa\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2004).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Urethral stricture disease, fibrosis, ECM remodeling, and inflammation.","lastPublishedDoi":"10.21203/rs.3.rs-9307477/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9307477/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"(248 words) Background: Urethral stricture disease (USD) is marked by inflammation with subsequent tissue fibrosis that disrupts urinary flow. Recent studies suggest lower urinary tract biome dysbiosis increases proinflammatory cytokines, impeding tissue repair as well as promoting fibrotic scarring of the urethra. Despite these insights, the comprehensive molecular mechanisms underlying the formation, progression, and recurrence of the USD remain unclear. We aim to identify novel molecular targets and designate pathways contributing to USD, thereby identifying potential targets for future therapeutic interventions. Methods: We performed a comprehensive multi-modal analysis in USD patient urine and scar tissues. Urinary cytokines were assayed, transcriptome profiling and pathway enrichment were performed, and network mapping identified fibrotic hubs. Biomechanical tissue stiffness was quantified by atomic force microscopy (AFM), and protein and histological validation employed both immunostaining and Western blotting. Results: IL-1β, IL-6, IL-8, TNF-β, IL-10 were significantly elevated in USD. Transcriptomic profiling revealed 745 differentially expressed genes, with enrichment in ECM organization, cytokine storm, TGF-β, integrin, IL-17A, WNT/β-catenin. ECM organization and cytokine storm are identified as central interactive hubs, dominated by collagen and fibrogenic regulators such as SMAD3 and TGF-β1. Tissue stiffness increased threefold in USD tissues compared to controls, highlighting ECM remodeling. Immunostaining demonstrated enhanced vimentin, elastin, COL1, and TGF-β expression, along with Western blot studies validating elevated protein levels. Conclusion: The integrative approach evaluating pathway enrichment with transcriptome profiling reveals novel interconnections between mechanisms of inflammation, matrix remodeling, and mechanotransduction driving USD. The findings provide a mechanistic foundation for individualized models and therapeutic targets. 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