Platelet-Rich Plasma (PRP), a core biotherapeutic material in regenerative medicine, exhibits unique advantages in wound healing and tissue regeneration owing to its high concentrations of platelets and diverse bioactive factors, including albumin, fibrinogen, globulins, and growth factors such as Transforming growth factor-β1 (TGF-β1), Platelet-derived growth factor (PDGF), and Vascular endothelial growth factor (VEGF) (Everts et al., 2024). However, the paradoxical bidirectional regulatory effects observed in its clinical application have garnered increasing attention: while PRP accelerates wound healing by promoting cell proliferation, angiogenesis, and ordered collagen deposition, it may also induce hypertrophic scars or even keloids due to excessive fibroblast activation and dysregulated extracellular matrix (ECM) metabolism (Chen et al., 2018; Ebrahimi et al., 2022). This bidirectional effect underscores an urgent unmet clinical need: the lack of mechanistic understanding of PRP’s scar-modulating pathways has prevented the development of precision strategies to maximize its therapeutic potential while mitigating fibrotic risks. Current research remains limited to broad biochemical signaling or generic ECM remodeling (Yang and Zhang, 2025; Wu et al., 2025), with no focus on the mechanotransduction networks that bridge PRP’s biological and physical effects on scar tissue.

Recent advances in mechanotransduction research have shown that cellular sensing and response to matrix mechanical cues (e.g., stiffness, tension) are critical regulators of ECM metabolism and scar fate. Among these, Piezo1—the first identified mechanosensitive cation channel in eukaryotes (non-selective, permeable to Na⁺, Ca²⁺, and other ions) (Fang et al., 2021; Coste et al., 2010)—is overexpressed in scar tissue, responds to mechanical stretch, and drives fibroblast activation and hypertrophic scar formation (He et al., 2021; Rennekampff et al., 2024). The interplay between its activation and YAP/TAZ nuclear translocation serves as the central mechanism by which mechanical and certain chemical signals influence scar outcomes (Hasegawa et al., 2021; Liu et al., 2021; Rashidi et al., 2025). In skin fibrosis, Piezo1 forms a positive feedback loop by sensing tissue stiffness: its upregulation promotes a fibroblast proliferative phenotype, whereas Piezo1-knockout fibroblasts lose their fibrotic traits even on high-stiffness substrates (He et al., 2024; Li et al., 2022). Piezo1-YAP/TAZ is consistently implicated in scar pathogenesis: Piezo1 is overexpressed in hypertrophic scar/keloid fibroblasts and YAP/TAZ nuclear translocation directly promotes fibroblast activation and ECM deposition (He et al., 2021; Rennekampff et al., 2024; Rashidi et al., 2025). No other pathway has been shown to integrate PRP’s dual biochemical-mechanical actions, making it the most relevant and translatable target for optimizing PRP therapy. Beyond skin, Piezo1 has been implicated in pulmonary fibrosis (Xu et al., 2025), cardiac fibrosis (Jin et al., 2024), and liver fibrosis (Wang et al., 2024), suggesting its broader role in mechanotransduction-driven fibrotic diseases. However, its mechanistic contribution may vary across organs and contexts.

Previous studies have suggested that PRP may activate or synergize with the Piezo1 channel via its abundant growth factors and potential lipid components, concurrently triggering critical Ca²⁺ signaling cascades that drive angiogenesis, cell proliferation, differentiation, and matrix remodeling—ultimately promoting the regeneration of damaged myocardial tissue (Alharbi et al., 2022). Regarding whether PRP can directly activate the Piezo1 channel, current evidence lacks direct experimental validation; however, indirect correlations and theoretical support have been proposed: the platelet plasma membrane in PRP may supply phosphatidylinositol bisphosphate (PIP₂), a lipid molecule recognized as a co-factor for Piezo1 channel activation (Alharbi et al., 2022; Smith et al., 2025; Yang et al., 2004; Borbiro et al., 2015-02).

Despite the well-established pro-regenerative effects of PRP, a critical knowledge gap persists in understanding whether PRP modulates fibroblast behavior and scar progression through the Piezo1-mediated mechanotransduction pathway. Based on our understanding of PRP’s active components, Piezo1’s functional roles (mechanosensing and pro-fibrotic activity), and their established regulatory crosstalk, we propose the following plausible hypothesis: PRP bidirectionally regulates scar formation by activating the Piezo1 channel on fibroblast surfaces, thereby modulating fibroblast proliferation, differentiation, and ECM metabolism. This framework not only clarifies PRP’s molecular mechanism of action but also provides a targeted strategy to optimize clinical outcomes (e.g., Piezo1 inhibitors, injection parameter tuning), filling the unmet need for precision anti-scar therapies.

We propose that PRP bidirectionally modulates fibroblast function and scar progression by targeting the Piezo1-YAP/TAZ mechanotransduction axis via multidimensional biological effects (Figure 1). During physiological repair, this modulation attenuates scar formation; during pathological fibrosis, it promotes the development of hypertrophic scars or keloids. We further hypothesize that PRP regulates the Piezo1 channel through the following mechanisms:

TGF-β1 secreted by PRP upregulates Piezo1 expression/activity, and the two interact via positive/negative feedback loops to modulate scar formation (Zhao et al., 2022; Holt et al., 2025; Yang et al., 2025; Cai et al., 2023).

The core pathological process of hypertrophic scarring (e.g., in skin wounds and visceral organs like the lung or liver) involves excessive fibroblast activation driven by dysregulated mechanotransduction pathways (Griffin et al., 2021) and aberrant ECM deposition orchestrated by profibrotic signaling hubs such as YAP/TAZ in pulmonary fibrosis (Papavassiliou et al., 2024). As a mechanosensitive ion channel, Piezo1 primarily regulates cellular functions (e.g., fibroblast proliferation, collagen secretion) by sensing extracellular mechanical cues (e.g., tissue tension, matrix stiffnes) or indirectly via growth factor signaling (He et al., 2024; Li et al., 2022). These functions exhibit bidirectional roles in physiological repair and pathological fibrosis—findings that strongly support the feasibility of targeting Piezo1 for scar therapy. Piezo1 activation in physiological tissue repair occurs through physiological mechanical cues​ (e.g., wound-edge contraction, collagen matrix remodeling) and regulated growth factor signaling. Moderate Piezo1 activation, as part of fibroblast functional regulation, facilitates normal tissue healing and reduces scar overgrowth (Rashidi et al., 2025; Emig et al., 2021). In contrast, pathological fibrosis arises from a synergistic interplay between Piezo1 hyperactivation (triggered by persistent mechanical stretch or excess profibrotic factors) and other pathological elements (e.g., chronic inflammation, aberrant ECM deposition). Activated Piezo1 further amplifies TGF-β1-downstream profibrotic signals via calcium signaling (forming a positive feedback loop) and activates pathways like YAP/TAZ. This drives uncontrolled fibroblast proliferation and excessive ECM deposition, potentially promoting hypertrophic scar or keloid formation (He et al., 2024; Bartoli et al., 2022).

The biological effects of PRP depend primarily on bioactive molecules released upon platelet activation: beyond growth factors, these include the fibrin scaffold formed post-activation. This scaffold not only provides physical support for cell migration/adhesion but also modulates cell behavior via mechanical properties (e.g., matrix stiffness) (Zhou et al., 2023). Based on current mechanistic insights, PRP bidirectionally regulates fibroblast function and scar progression by targeting the Piezo1-YAP/TAZ mechanotransduction axis via multidimensional effects. Below, we elucidate the underlying mechanisms:

The hypothesis that PRP bidirectionally modulates scar formation by targeting the Piezo1-YAP/TAZ mechanotransduction axis via multidimensional biological effects reveals the synergism of biochemical factors, tissue mechanics, and cellular mechanotransduction in wound repair—offering critical insights for both basic research and clinical translation:

To systematically validate the hypothesis, a hierarchical experimental strategy can be designed, integrating in vitro mechanistic dissection, in vivo model testing, and multi-pathway synergistic blockade—centered on three core mechanisms: the TGF-β1-Piezo1 positive feedback loop, matrix mechanical regulation, and direct activation by PRP injection forces (Table 1).

For the TGF-β1-Piezo1 positive feedback loop, in vitro studies can use human skin fibroblasts (HSFs) stimulated with PRP (containing endogenous TGF-β1). TGF-β1 concentration changes can first be quantified via ELISA, while Piezo1 mRNA/protein expression can be analyzed using qPCR and Western blotting (WB) to explore their correlation. To confirm the TGF-β1→Piezo1 axis, TGF-β1 can be neutralized with antibodies or its receptor I (TβRI) can be knocked down via siRNA; reduced Piezo1 expression can validate upstream control. Calcium imaging can monitor Ca²⁺ influx upon Piezo1 activation, while Smad2/3 phosphorylation assays can indirectly link Piezo1 function to TGF-β signaling (Zhao et al., 2022; Yang et al., 2025). In vivo, a mouse scar model can be generated, with groups receiving PRP alone or PRP plus TGF-β1 neutralizing antibody. Immunofluorescence co-localization can assess Piezo1/TGF-β1 subcellular distribution, and WB for YAP nuclear translocation (a mechanotransduction hallmark) can test whether this feedback drives fibrosis (Rashidi et al., 2025; Liao et al., 2025; Xue et al., 2025; Peng et al., 2025).

To evaluate matrix mechanical regulation, in vitro experiments can use collagen gels with stiffness gradients to mimic physiological/pathological microenvironments. HSFs co-cultured with PRP on these gels can be analyzed via atomic force microscopy (AFM) to quantify local matrix stiffness changes in the pericellular microenvironment surrounding individual fibroblasts (rather than bulk/overall stiffness of the gel), as AFM enables high-resolution nanomechanical mapping of pericellular matrix stiffness with spatial precision at the single-cell scale (Shioka et al., 2024; Adam et al., 2025). Calcium imaging will be employed to monitor Piezo1 channel activity in response to these localized mechanical cues (Xue et al., 2025; Peng et al., 2025), and Western blotting (WB) to assess nuclear translocation of YAP (a downstream effector of Piezo1 mechanotransduction) (Rashidi et al., 2025).

To test if matrix stiffness acts via Piezo1-YAP, cells can be treated with a lysyl oxidase (LOX) inhibitor (reducing stiffness by blocking collagen cross-linking) (Yu et al., 2025), and changes in Piezo1 activity and YAP translocation can be compared. In vivo, PRP-treated mouse scars can be assessed post-surgery: AFM can measure tissue stiffness, immunohistochemistry (IHC) can quantify collagen density (Masson’s trichrome) and α-SMA (fibroblast activation) to grade fibrosis (Lin et al., 2025), and immunofluorescence double labeling can evaluate Piezo1/YAP co-localization (Zhuang et al., 2024). These studies can elucidate how Piezo1 senses matrix stiffness to activate YAP signaling, driving fibrosis.

For direct activation by injection mechanical force, in vitro experiments can simulate PRP injection using a pressure pump, combined with nanopipette tension manipulation (Lüchtefeld et al., 2024) and porous cell stretching systems (Zhu et al., 2025) for precise force control. Piezo1-GFP conformational fluorescence imaging can be used to observe Piezo1 channel opening: the GFP fusion tag reports on Piezo1’s mechanosensitive structural rearrangements upon channel gating (this is distinct from constitutive GFP fluorescence that only indicates Piezo1 protein presence, with no distinction between closed and open states) (Mulhall et al., 2023). Calcium imaging can measure Piezo1-dependent Ca²⁺ influx, and Gd³⁺ pretreatment can confirm Piezo1 as the key mechanosensor mediating this mechanotransduction response (Malko et al., 2023). In vivo, low-vs. high-rate PRP injections can create mechanical gradients; WB can detect Piezo1 membrane levels, and IHC can analyze collagen deposition to link membrane tension to mechanosensing (Mills et al., 2022; Sun et al., 2022), confirming a positive correlation between force rate and fibrosis. Finally, combined in vitro blockade (neutralizing antibodies, LOX inhibitors, Gd³⁺) and in vivo combination therapies can validate that these three pathways synergize via a TGF-β1→matrix remodeling →mechanical force cascade to regulate the Piezo1-YAP axis.

Collectively, this hypothesis can establish a novel mechano-biochemical framework for PRP research—advancing beyond single-factor analyses to capture interplay between biochemical signals, matrix mechanics, and mechanical forces. Validation can optimize PRP clinical use (e.g., adjusting injection parameters, combining with Piezo1 inhibitors) and can provide a theoretical basis for precision scar therapy targeting the Piezo1-YAP axis.

PRP is widely used in regenerative medicine for its ability to enhance tissue repair, yet its precise molecular effects on scar formation remain unclear. Recent research underscores the importance of mechanosensitive pathways—specifically the Piezo1 ion channel and the YAP/TAZ signaling axis—in wound healing and fibrosis. Within scar tissue, Piezo1 functions as a crucial amplifier of mechanical signals, working synergistically with other pathways to intensify YAP/TAZ-dependent fibrotic processes (He et al., 2021; Rennekampff et al., 2024). The bidirectional regulation hypothesis of PRP in scar progression—where it suppresses scarring during physiological repair and promotes fibrosis in pathological conditions—offers a novel lens to interpret its intricate biological effects. At its core, this mechanism hinges on targeting the Piezo1-YAP/TAZ axis via multidimensional signals (biochemical factors, matrix mechanics, and mechanical forces), with aberrant activation of this axis already recognized as a key driver of fibrosis. The Piezo1-YAP/TAZ axis is not proposed as the “sole” mechanism but as the integrative hub that unifies PRP’s multidimensional effects (biochemical, mechanical, and physical). Unlike other pathways (e.g., PI3K/Akt, Wnt) that primarily mediate isolated biochemical signals, Piezo1-YAP/TAZ uniquely transduces both soluble factors (PRP-derived TGF-β1) and mechanical cues (ECM stiffness, injection forces)—two interconnected drivers of scar formation that were previously studied in isolation (Arioka et al., 2025). However, direct associations between PRP and Piezo1 remain poorly characterized: while PRP contains profibrotic factors like TGF-β1, it also harbors anti-inflammatory (e.g., IL-1Ra) and proangiogenic (e.g., VEGF) factors that may modulate scar outcomes through distinct pathways. This functional pleiotropy likely underlies the pronounced “dose-time-scar type” dependency of PRP’s effects—explaining the controversies in clinical efficacy [e.g., some studies report improved atrophic scars (Zare et al., 2025), whereas others note exacerbated hypertrophic scars (Chen et al., 2018)].

Mechanistically, the synergistic interplay of three pathways may underpin PRP’s bidirectional regulation: the TGF-β1-Piezo1 positive feedback loop, matrix mechanical remodeling, and direct activation by injection mechanical force. In pathological scars, excessive TGF-β1 release (e.g., from high-concentration PRP or repeated injections) may drive persistent Piezo1 activation, which in turn amplifies fibroblast proliferation and collagen deposition via YAP/TAZ—creating a “fibrosis-positive feedback amplification” vicious cycle. Conversely, in physiological repair, moderate TGF-β1 levels keep this feedback tightly controlled (e.g., through TGF-β1 receptor desensitization or antagonism by antifibrotic factors), restricting Piezo1 to transient activation that maintains ECM homeostasis. Matrix mechanical remodeling, by altering tissue stiffness (e.g., increased stiffness in pathological scars from PRP-induced collagen cross-linking, or decreased stiffness in physiological repair from ordered collagen alignment), directly modulates Piezo1’s open probability: stiff matrices excessively activate the Piezo1-YAP axis to promote fibrosis, while moderate stiffness limits activation to prevent scar hyperplasia. The effect of mechanically induced Piezo1 activation also varies with injection parameters: low-dose, slow injection may trigger transient Piezo1 activation (supporting physiological repair), whereas high-dose, rapid injection delivers sustained mechanical stimulation that induces Piezo1 desensitization or dephosphorylation—exacerbating abnormal YAP/TAZ nuclear translocation (driving pathological scarring).

Among the numerous components of PRP, both TGF-β1 and PIP₂ can directly modulate Piezo1 (Liu et al., 2021; Alharbi et al., 2022; Smith et al., 2025; Yang et al., 2004; Borbiro et al., 2015-02; Chen et al., 2025), while other components may influence certain aspects of the Piezo1-YAP/TAZ axis (Table 2). Research indicates that VEGF indirectly activates Piezo1 through a VEGF-myc-myosin 1b-Piezo1 axis (Lv et al., 2024). In this pathway, VEGF upregulates Myosin 1b expression, and the mechanical force generated by myosin contraction subsequently activates Piezo1. Furthermore, in addition to acting through the Piezo1-YAP/TAZ axis, PRP can also accelerate wound healing and re-epithelialization by releasing growth factors and exosomes that activate YAP (Guo et al., 2017; Zhang et al., 2020), which in turn influences scar formation. The YAP/TAZ axis can be activated by increased ECM stiffness and shear stresses independently of Piezo1. Conversely, in hypertrophic scars, PRP may reduce connective tissue growth factor (CTGF) via TGF-β1 negative feedback, potentially limiting excessive fibrosis (Nam and Kim, 2018). Blocking Piezo1 or modulating YAP/TAZ activity can reduce scar formation, suggesting therapeutic targets for controlling fibrosis (He et al., 2021; Rennekampff et al., 2024).

Despite its plausibility, the hypothesis currently lacks direct experimental validation: no studies have reported how PRP treatment affects Piezo1 expression/function in scar-associated fibroblasts, nor clarified whether PRP’s profibrotic effects depend on Piezo1. In vivo, the correlation between Piezo1 levels in PRP-treated scar tissue and therapeutic efficacy remains unverified. Future investigations should prioritize defining the regulatory weights of PRP components on Piezo1 and distinguishing synergistic/antagonistic interactions between profibrotic and antifibrotic factors; validating the necessity of Piezo1 in PRP-induced fibroblast activation; comparing, in animal models, the effects of different PRP preparations (concentration, activation method) combined with Piezo1 inhibitors on scar size, stiffness, and collagen deposition to establish optimal intervention parameters; and enrolling clinical cohorts to correlate pre-vs. post-treatment Piezo1 expression in scar tissue with clinical outcomes (improvement vs. worsening)—thereby translating the hypothesis into precision therapy.

Currently, no direct evidence confirms that PRP influences scar formation by regulating the Piezo1–YAP/TAZ axis. However, given the roles of PRP-derived TGF-β1 and Piezo1, along with their potential interaction, we hypothesize that PRP bidirectionally regulates fibroblast function and scar progression through this axis via multiple biological effects. Under physiological repair conditions, it may attenuate scarring, whereas in pathological fibrosis, it could promote hypertrophic scars or keloids. PRP might modulate Piezo1 through TGF-β1 feedback, matrix mechanical properties, PIP2 availability, and mechanical forces induced by injection. The proposed “PRP → multidimensional effects on Piezo1–YAP/TAZ → scar modulation” pathway requires experimental validation. Clarifying this mechanism is essential for understanding PRP efficacy, refining therapeutic protocols, and developing anti-scar strategies.