The role of Piezo1 as a mechanotransduction hub in bladder fibrosis: therapeutic targeting strategies and challenges—a narrative review

Introduction

Background

Bladder dysfunction, particularly in conditions such as neurogenic bladder (NGB) and partial bladder outlet obstruction (PBOO), severely impairs patient quality of life and imposes a substantial global healthcare burden (1,2). The core pathophysiological driver of these conditions is sustained pressure overload and/or neuromodulatory impairment, which ultimately triggers complex structural and functional remodeling of the bladder wall (3).

Within this remodeling cascade, bladder fibrosis emerges as a critical, often irreversible terminal event. This pathological process is defined by excessive extracellular matrix (ECM) deposition, fibroblast-to-myofibroblast transdifferentiation, and progressive tissue stiffening—collectively compromising bladder compliance and reducing its storage capacity (4). Notably, bladder fibrosis is not restricted to NGB or PBOO; emerging evidence positions it as a shared pathological endpoint in diverse conditions, including essential hypertension and chemical-induced bladder injury (e.g., ketamine-associated bladder damage), underscoring its broad relevance as a therapeutic target (5).

Rationale and knowledge gap

Despite growing insights into these downstream pathological events (e.g., ECM accumulation, myofibroblast activation, tissue stiffening), current therapeutic approaches remain predominantly focused on symptom management (e.g., muscarinic antagonists or β3-adrenoceptor agonists to enhance bladder storage) or targeting late-stage fibrotic signaling pathways (e.g., TGF-β, NF-κB). These strategies rarely reverse established structural damage, leading to limited long-term clinical efficacy (6). Thus, identifying and targeting upstream “master regulators” that initiate and perpetuate the fibrotic cascade has become an urgent priority for developing transformative anti-fibrotic therapies.

In recent years, advances in mechanobiology have offered a novel framework to understand bladder pathobiology. As an organ that undergoes continuous filling-voiding cycles, bladder cells are persistently exposed to mechanical stimuli. Mechanotransduction—the process by which cells sense mechanical forces and convert them into biochemical signals—plays a pivotal role in both maintaining tissue homeostasis and driving disease progression. Among mechanosensitive ion channels, the Piezo family (with Piezo1 as the primary isoform of interest) has emerged as a key research focus. As essential cellular “mechanosensors”, Piezo1 has been implicated as a critical initiator of fibrotic processes across multiple tissues (7,8).

Objective

This review seeks to: (I) systematically define the role of Piezo1 as a central mechanotransduction hub in bladder fibrosis; (II) contextualize its molecular mechanisms within the pathological progression of bladder fibrosis; and (III) comprehensively evaluate the opportunities and challenges of targeting Piezo1 for the development of novel anti-fibrotic therapeutic strategies. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0287/rc).

Methods

A comprehensive search of the PubMed, Web of Science, and Scopus databases was performed to identify studies published between January 2010 and June 1, 2026. The search strategy is summarized in Table 1.

Bladder fibrosis: a common pathway to lower urinary tract dysfunction (LUTD)

Bladder fibrosis is defined by excessive ECM accumulation, causing bladder wall stiffening and scarring—ultimately impairing compliance, reducing capacity, and inducing severe lower urinary tract symptoms (LUTS) (3,9-12). More broadly, the lower urinary tract is governed by highly integrated signalling networks, which may help explain why structural remodeling can translate into heterogeneous functional symptoms and why single-target interventions often face translational barriers (13). Severe cases lead to vesicoureteral reflux, hydronephrosis, and irreversible renal failure due to elevated intravesical pressure (14). Diverse etiologies (PBOO from BPH/urethral strictures, NGB from SCI/diabetes, chronic inflammation, ketamine-induced cystitis) converge on sustained bladder wall stress, exposing cells to supraphysiological mechanical forces or chronic inflammation (15-18). In this context, pathological bladder stress is increasingly recognized to induce adaptive and maladaptive shifts in ion channel expression, supporting the concept that channel remodeling is an important component of bladder disease progression (19).

At the cellular level, fibrosis is driven by resident fibroblast activation and transdifferentiation into α-smooth muscle actin (α-SMA)-positive myofibroblasts—key producers of ECM (predominantly type I/III collagens) (20-22). ECM deposition replaces functional smooth muscle, forming a vicious cycle where stiffened matrix further promotes fibroblast activation; the TGF-β1 cascade is a central downstream regulator (5,23-25). Current therapies only alleviate symptoms or address primary causes (e.g., obstruction relief) but fail to reverse fibrosis (26). Identifying upstream molecular sensors (e.g., mechanosensitive ion channels like Piezo1) that translate pathological cues into pro-fibrotic signaling remains a critical unmet need.

Piezo1: the foundation of mechanotransduction and its pivotal role in bladder fibrosis

The discovery of Piezo channels and their fundamental function as mechanosensors

The identification of the Piezo protein family marked a transformative breakthrough in mechanobiology, resolving long-standing questions about how eukaryotic cells sense and respond to physical mechanical cues (7). Unlike traditional ion channels that rely on chemical ligands for activation, Piezo proteins were characterized as the core pore-forming subunits of mechanically activated cation channels—specialized molecular machinery that directly converts physical forces into electrochemical signals in multicellular eukaryotes (27).

Piezo1, a large transmembrane protein with a molecular weight exceeding 250 kDa, features a distinct homo-trimeric structure that assembles into a three-bladed, propeller-like conformation spanning the cell membrane (Figure 1) (28). This unique architecture is not merely structural: each “blade” of the propeller contains multiple transmembrane helices that act as “mechanical antennae”, enabling Piezo1 to detect and discriminate between diverse mechanical stimuli. For instance, when the bladder wall stretches during filling, the membrane tension-induced deformation of these helices triggers a conformational shift in the channel, while changes in ECM stiffness (a hallmark of early fibrosis) are sensed via Piezo1’s interaction with cytoskeletal proteins, further modulating its gating properties. Even fluid shear stress—relevant to urine flow dynamics in the bladder—can induce Piezo1 activation by altering membrane curvature at the channel’s pore region.

Figure 1 Schematic of Piezo1-mediated pro-fibrotic signaling in bladder fibroblasts. Sustained elevation of intravesical pressure upregulates Piezo1 expression in bladder resident fibroblasts. Under mechanical stretch (mimicking bladder overdistension), Piezo1 is activated in synergy with the intracellular actomyosin network, triggering Ca²⁺ influx into fibroblasts. This Ca²⁺ signal bifurcates into two complementary pro-fibrotic pathways: (I) inhibition of the Hippo pathway, which reduces phosphorylation of LATS1/2, leading to dephosphorylation, nuclear translocation, and activation of YAP1; (II) promotion of TGF-β1 secretion, which activates an auto-activation loop to drive canonical Smad2/3 phosphorylation and subsequent nuclear entry. Ultimately, nuclear YAP1 and phosphorylated Smad2/3 synergistically initiate transcription of pro-fibrotic genes, inducing the transdifferentiation of fibroblasts into α-SMA-positive myofibroblasts and excessive secretion of ECM components (e.g., type I/III collagens). These events collectively culminate in bladder fibrosis. α-SMA, α-smooth muscle actin; ECM, extracellular matrix.

Upon mechanical activation, the Piezo1 channel opens to form a non-selective cation pore, permitting the influx of cations into the cell along their electrochemical gradient. While Na⁺, K⁺, and Mg²⁺ contribute to this ion flow, Ca²⁺ influx is functionally dominant: as a universal second messenger, Ca²⁺ rapidly diffuses through the cytoplasm to activate downstream signaling cascades. These cascades include the activation of calcium-dependent kinases (e.g., protein kinase C), the modulation of transcription factors (e.g., NFAT), and the regulation of cytoskeletal remodeling—all of which collectively translate physical mechanical forces into biochemical signals that govern critical cell fate decisions, such as proliferation, differentiation, and ECM secretion.

The central role of Piezo1 in the pathogenesis of bladder fibrosis

In the context of bladder pathophysiology, Piezo1’s function as an upstream mechanosensor has become increasingly well-defined, with evidence highlighting its role as a “gatekeeper” for initiating fibrotic remodeling. Piezo1 expression is well-documented in the urothelium, where it participates in physiological mechanotransduction and lower urinary tract interoception (28). Importantly, mounting preclinical studies demonstrate its pathological relevance: in models of sustained bladder pressure elevation—most notably PBOO—Piezo1 expression is significantly upregulated in key bladder tissues, including the lamina propria (29). This upregulation is not uniform: in lamina propria fibroblasts (the primary cell type driving ECM deposition), Piezo1 expression levels increase by two- to three-fold within 72 hours of sustained pressure overload, while urothelial Piezo1 upregulation occurs earlier (within 24 hours), suggesting a sequential activation of Piezo1-dependent signaling across bladder cell layers. In the urothelium, this Piezo1 activation is critically linked to inflammation and epithelial-mesenchymal transition (EMT); elevated intracellular Ca²⁺ triggers ATP and ROS release, which subsequently activates the NLRP3 inflammasome, accelerating mucosal fibrosis during bladder outlet obstruction (30).

Critically, this upregulation of Piezo1 resets the sensitivity threshold of bladder cells to mechanical stimuli: fibroblasts from pressure-overloaded bladders exhibit Piezo1 activation at lower levels of stretch (approximately 10% membrane deformation) compared to fibroblasts from normal bladders (which require ~20% deformation), creating a permissive microenvironment for fibrotic initiation. In the context of the bladder, pathologically elevated mechanical forces—such as high hydrostatic pressure (HHP) and mechanical stretch mimicking cyclic overdistension in PBOO or NGB—directly drive the transition of bladder resident fibroblasts toward a pro-fibrotic phenotype via Piezo1 activation (31,32). Recent evidence has confirmed that Piezo1 acts as the critical mechanosensor in this process, where its activation in urinary system fibroblasts specifically induces myofibroblast differentiation and ECM production (25). Furthermore, complementary evidence from non-bladder tissues corroborates that stretch-mediated fibroblast activation via Piezo1 is a conserved pathological mechanism across multiple organ systems (27). This activation is not independent of the cytoskeleton: the intracellular actomyosin network, which undergoes reorganization in response to stretch, physically interacts with the cytoplasmic domain of Piezo1, amplifying mechanical signal transduction. Specifically, stretch-induced contraction of actin filaments pulls on Piezo1’s cytoplasmic tails, stabilizing the channel’s open conformation and prolonging Ca²⁺ influx—this synergy between Piezo1 and the actomyosin network ensures that even transient mechanical stimuli are converted into sustained pro-fibrotic signals (25).

The Ca²⁺ influx triggered by Piezo1 activation bifurcates into two complementary, yet interdependent, pro-fibrotic pathways: the TGF-β1/Smad pathway and the Hippo/YAP1 pathway. In the first pathway, Piezo1-mediated Ca²⁺ influx activates calmodulin-dependent protein kinase II (CaMKII), which phosphorylates the transcription factor CREB. Phosphorylated CREB then translocates to the nucleus and binds to the promoter region of the TGF-β1 gene, upregulating its expression and secretion. The secreted TGF-β1 then binds to its receptors on the fibroblast surface, initiating an auto-activation loop that phosphorylates Smad2/3. Phosphorylated Smad2/3 forms a complex with Smad4, which translocates to the nucleus to drive the transcription of pro-fibrotic genes, including those encoding type I/III collagens and α-SMA—key markers of fibroblast-to-myofibroblast transdifferentiation.

Concurrently, Piezo1 activation potently drives the fibrotic program via the Hippo pathway. The Ca²⁺ influx from Piezo1 channels inhibits the activity of the Hippo pathway kinases LATS1/2 by activating the phosphatase calcineurin, which dephosphorylates LATS1/2 and reduces its kinase activity. Inactive LATS1/2 fails to phosphorylate YAP1, allowing dephosphorylated YAP1 to translocate to the nucleus. Nuclear YAP1 then partners with TEAD transcription factors to upregulate genes involved in fibroblast proliferation (e.g., cyclin D1) and ECM production (e.g., connective tissue growth factor, CTGF). Furthermore, recent evidence highlights that this Piezo1-mediated YAP1 activation drives metabolic reprogramming in bladder fibroblasts; specifically, YAP1 upregulates glutaminase 1 (GLS1) to enhance glutamine metabolism, a process essential for fibroblast proliferation and activation under HHPs (33). Supporting the plausibility of a stiffness-driven feed-forward mechanism, a stiffness-dependent Piezo1/ITGB1–Ca²⁺/YAP signalling loop has also been reported in bladder carcinoma, suggesting that matrix stiffening may further amplify Piezo1/YAP activation in bladder pathology (34). Importantly, these two pathways exhibit cross-talk: nuclear YAP1 can directly bind to the TGF-β1 promoter to further enhance its expression, while TGF-β1-induced Smad2/3 activation can stabilize YAP1 in the nucleus by inhibiting its degradation. This synergistic crosstalk ensures the robust activation of the fibrotic program, positioning Piezo1 as the central hub of the bladder fibrosis signaling network (31,35).

Precisely targeting Piezo1: challenges, strategies, and future outlook

The challenge of targeting Piezo1: a double-edged sword

While evidence supporting Piezo1 as a pro-fibrotic master switch in the bladder is compelling, its translation into a clinical therapeutic target is hindered by two interconnected challenges rooted in the Piezo family’s functional pleiotropy and tissue-wide expression—creating a “double-edged sword” for intervention.

First, the functional overlap and structural homology between Piezo1 and Piezo2 (the only other member of the Piezo family) pose a major barrier to selectivity. Piezo2 is not merely a “sibling” channel but an indispensable mediator of normal urinary tract physiology: in the urothelium, Piezo2 is localized to the apical membrane of umbrella cells, where it senses bladder filling-induced stretch and triggers the release of ATP—a key neurotransmitter that initiates sensory signaling to the spinal cord (28,36). In dorsal root ganglion (DRG) sensory neurons innervating the bladder, Piezo2 further amplifies this signal by transducing mechanical stimuli into action potentials, ultimately integrating with central nervous system circuits to generate the “urge to void” (37). This dual role in peripheral sensing and neural signaling means that non-selective Piezo inhibitors (e.g., compounds targeting the conserved pore domain shared by Piezo1 and Piezo2) would not only block Piezo1-mediated fibrosis but also disrupt Piezo2-dependent urinary sensation. Preclinical studies in Piezo2-knockdown mice support this risk: these animals exhibit blunted voiding reflexes, increased bladder capacity, and occasional urinary retention—side effects that would be clinically unacceptable for patients already burdened by bladder dysfunction (36).

Second, Piezo1’s broad tissue expression and involvement in essential physiological processes beyond the bladder raise concerns about systemic toxicity. Beyond its role in fibrosis, Piezo1 acts as a “physiological sensor” in multiple organ systems: in the cardiovascular system, endothelial Piezo1 detects fluid shear stress in arteries, triggering the release of nitric oxide (NO) to regulate vascular tone—an effect critical for maintaining blood pressure homeostasis (38). In renal glomerular podocytes, Piezo1 senses changes in hydrostatic pressure to modulate filtration barrier permeability, while in the lung, alveolar epithelial Piezo1 mediates stretch-induced surfactant secretion (38). Consistent with its broad mechanosensory roles beyond the urinary tract, Piezo1 is also implicated in exercise-induced cardiovascular adaptation, reinforcing concerns regarding non-selective systemic Piezo1 modulation (39).This widespread functional relevance implies that systemic administration of a Piezo1 inhibitor could disrupt these processes: for example, blocking endothelial Piezo1 might reduce NO production, leading to vasoconstriction and elevated blood pressure, while inhibiting renal Piezo1 could impair glomerular filtration. Even subtle off-target effects in these organs could limit clinical utility, as patients with bladder fibrosis (e.g., those with PBOO or diabetes) often have comorbid cardiovascular or renal conditions. Collectively, these challenges converge on a central “therapeutic dilemma”: how to selectively silence Piezo1’s pathological pro-fibrotic activity in the bladder while preserving its physiological functions in other tissues and avoiding interference with Piezo2.

Potential strategies for targeting Piezo1

To overcome the “therapeutic dilemma”, future intervention strategies must move beyond non-selective channel blockade and embrace precision-focused approaches tailored to Piezo1’s unique biology in the bladder.

A foundational strategy is the optimization of local drug delivery—an approach that leverages the bladder’s anatomical accessibility to minimize systemic exposure. Intravesical instillation, the gold standard for local bladder therapy, involves delivering drug formulations directly into the bladder lumen via a catheter, where the agent can interact with the urothelium and underlying lamina propria (the primary sites of Piezo1 upregulation in fibrosis) (40). To enhance efficacy and reduce washout (a major limitation of conventional instillations), researchers are exploring specialized drug carriers: lipid-based nanoparticles can fuse with the urothelial cell membrane to prolong drug retention, while hydrogel formulations [e.g., thermosensitive poly(ethylene glycol)-poly(lactic-co-glycolic acid) gels] solidify at body temperature to form a sustained-release depot. While specific nanoparticle-based Piezo1 modulators for the bladder are still under development, integrating existing Piezo1-targeting peptides (such as GsMTx4) with advanced intravesical delivery platforms (e.g., lipid nanoparticles or hydrogels) represents a highly promising future direction. Such a proposed strategy could maximize local drug concentrations in the urothelium and lamina propria to attenuate stretch-induced fibrosis, while strictly preventing systemic absorption and avoiding the off-target cardiovascular or renal risks associated with systemic Piezo1 blockade (38,41). Notably, Piezo1 has recently been leveraged as a mechanosensitive actuator for mechanically programmable intravesical drug delivery, providing proof-of-concept that bladder-local, stimulus-responsive therapeutic platforms may enhance efficacy while limiting systemic exposure (42).

At the molecular level, the development of highly selective Piezo1 modulators represents a more sophisticated approach. Traditional mechanosensitive channel blockers like GsMTx4 (a peptide derived from tarantula venom) suffer from poor selectivity: while GsMTx4 inhibits Piezo1 by binding to the channel’s extracellular domain, it also interacts with other stretch-activated channels (e.g., TRPV4, a cation channel involved in bladder inflammation) (43). To address this, researchers are focusing on allosteric modulators—compounds that bind to Piezo1’s unique intracellular or transmembrane allosteric sites (distinct from the conserved pore domain) to fine-tune its gating properties. For example, recent evidence that Piezo1 can transmit conformational signals beyond canonical ion permeation supports the possibility that future modulators may fine-tune its gating or downstream coupling rather than simply blocking the pore (44). This “tunable” modulation is critical: it allows for suppression of pro-fibrotic Ca²⁺ influx while preserving Piezo1’s role in maintaining tissue homeostasis.

Another innovative frontier is targeting Piezo1’s regulatory protein interactions—an approach that exploits the channel’s dependence on accessory proteins for functional activation. Piezo1 does not act in isolation: its activity is modulated by a network of interacting proteins, including cytoskeletal components (e.g., α-actinin, which links Piezo1 to actin filaments) and signaling adaptors (e.g., TRIP6, which bridges Piezo1 to TGF-β1 receptors) (45). Disrupting these interactions can selectively inhibit Piezo1’s pro-fibrotic activity: for instance, peptides that block the binding of α-actinin to Piezo1 reduce the channel’s activation by mechanical stretch (since the actomyosin network can no longer amplify the stretch signal) but do not affect Piezo1’s basal activity (45). Similarly, inhibiting the Piezo1-TRIP6 interaction disrupts the cross-talk between Piezo1 and the TGF-β1 pathway—blocking TGF-β1 secretion without altering Piezo1’s role in other signaling cascades. This strategy offers a “context-specific” advantage: by targeting interactions unique to the fibrotic microenvironment, it minimizes interference with Piezo1’s physiological functions in other tissues.

Finally, combining these strategies (e.g., local delivery of allosteric modulators) could further enhance precision. For example, encapsulating Piezo1 allosteric modulators in bladder-specific hydrogels would ensure that the drug acts only at the site of fibrosis, while the modulator’s selectivity ensures it targets only pathological Piezo1 activity—creating a “two-layered” approach to mitigate off-target effects.

Strengths and limitations

This review has several strengths. First, it provides a comprehensive synthesis of current evidence on Piezo1’s role as a mechanotransduction hub in bladder fibrosis, integrating molecular mechanisms with therapeutic implications. Second, the review covers the most recent literature (2010–2026), including emerging strategies such as allosteric modulators and local drug delivery systems. Third, by addressing both opportunities and challenges in targeting Piezo1, this review offers a balanced perspective for researchers and clinicians.

However, several limitations should be acknowledged. As a narrative review, we did not systematically assess the quality of included studies or perform a meta-analysis. The literature search, while comprehensive, may not have captured all relevant studies, particularly those published in non-English languages or as conference abstracts. Additionally, most evidence on Piezo1 in bladder fibrosis derives from preclinical animal models; human clinical data remain limited, which restricts the direct translational applicability of current findings. Finally, the therapeutic strategies discussed are largely in preclinical stages, and their clinical efficacy and safety profiles remain to be established. Furthermore, it is important to acknowledge a broader translational challenge in the field of LUTD. Historically, there is extensive literature identifying potential therapeutic targets based on single signaling pathways; however, effective targeting for very few of those has ultimately been achieved in the clinical setting. In addition, LUT function is modulated by systemic factors such as aging and diurnal rhythms, further increasing clinical heterogeneity and complicating translation from preclinical models (46). The multifaceted etiology of bladder fibrosis, combined with the structural complexity of human lower urinary tract physiology, means that preclinical success with targeted modulators (such as those aimed at Piezo1) does not guarantee clinical efficacy. Therefore, while Piezo1 presents a scientifically compelling upstream target, cautious optimism is warranted regarding its path to successful clinical translation.

Conclusions

In conclusion, evidence synthesized across the preceding sections confirms that Piezo1 is not only a key initiator of bladder fibrosis but also a therapeutic target that carries both notable challenges and substantial opportunities. Future research should prioritize two complementary directions: first, advancing the development of highly selective Piezo1 inhibitors or allosteric modulators—agents designed to address the “therapeutic dilemma” of distinguishing pathological (fibrosis-driving) Piezo1 activity from its physiological functions; second, concurrently leveraging advanced tools such as proteomics and chemically induced proximity techniques to systematically map the Piezo1 interactome and its downstream signaling pathways in bladder-specific cell types (e.g., resident fibroblasts, urothelial cells). This latter effort will yield critical mechanistic insights to guide the design of more precise, tissue-restricted intervention strategies (18,47).

The ultimate goal of these research endeavors is to develop “smart” therapeutics: interventions that can selectively dampen Piezo1-mediated pathological signaling in the bladder while preserving the channel’s essential physiological roles in other tissues (e.g., cardiovascular homeostasis, normal urinary sensation). By achieving this level of specificity, we can finally offer genuinely effective therapeutic hope to the vast population of patients suffering from bladder fibrosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0287/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0287/prf

Funding: This work was supported by the National Natural Science Foundation of China (grant No. 82200857).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0287/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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