IntroductionThe extracellular matrix (ECM) is increasingly recognized as an active biomechanical regulator of tissue homeostasis rather than a passive structural scaffold. Beyond providing architectural support, the ECM continuously transmits biochemical and mechanical information that governs cell proliferation, differentiation, migration, metabolism, survival, and immune responses1. Mechanical properties of the ECM—including stiffness, viscoelasticity, topography, and fiber organization—are tightly regulated under physiological conditions to maintain tissue integrity and coordinate regeneration following injury. However, pathological remodeling characterized by excessive collagen deposition, matrix crosslinking, altered fiber architecture, and progressive tissue stiffening fundamentally changes the mechanical landscape experienced by resident cells, driving persistent mechanotransductive signaling that contributes to cancer, fibrosis, chronic inflammatory disorders, allergic diseases, and cardiovascular pathology1. Cells interpret these extracellular mechanical cues through highly integrated mechanotransduction networks that physically couple the ECM to intracellular signaling machinery. Integrins, focal adhesion complexes, actomyosin contractility, and nuclear mechanosensing collectively convert mechanical forces into biochemical and transcriptional responses that regulate cell fate, inflammatory activation, and tissue remodeling2. Rather than acting independently of classical signaling pathways, mechanical stimuli cooperate extensively with inflammatory, metabolic, and growth factor signaling networks, allowing changes in tissue biomechanics to reshape cellular behavior across diverse physiological and pathological contexts.Among the central effectors of mechanotransduction, the Hippo pathway coactivators yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have emerged as major regulators of mechanically responsive transcription. Although YAP and TAZ share substantial structural and functional overlap and are often co-regulated by mechanical cues, they can also exert distinct, context-dependent effects because of differences in expression, transcriptional partnerships, and cellular functions. Therefore, YAP/TAZ is used in this review when their activities are overlapping or mechanistically inseparable, whereas individual effects are attributed specifically to YAP or TAZ where supported by the available evidence (Fig. 1). Under canonical Hippo signaling, activation of the mammalian ste20-like kinases 1/2 (MST1/2)—large tumor suppressor kinase 1/2 (LATS1/2) kinase cascade phosphorylates YAP and TAZ, promoting their cytoplasmic sequestration and degradation. In contrast, mechanical stimulation generated by increased ECM stiffness, focal adhesion maturation, cytoskeletal tension, or nuclear deformation can regulate YAP/TAZ through multiple interconnected mechanisms. Mechanical inputs may modulate the canonical MST1/2–LATS1/2 kinase cascade, but can also influence YAP/TAZ through integrin–focal adhesion signaling, RhoA–ROCK-dependent actomyosin tension, and nuclear mechanotransduction involving nuclear deformation and altered nuclear pore and chromatin states, thereby promoting YAP/TAZ nuclear localization and transcriptional activity3. Consequently, YAP and TAZ function as molecular integrators that connect tissue biomechanics with transcriptional responses controlling both physiological adaptation and disease progression. Importantly, YAP/TAZ signaling is highly context dependent. During embryonic development and normal tissue regeneration, transient activation of YAP/TAZ supports organogenesis, stem cell maintenance, wound healing, and restoration of tissue architecture4. In contrast, persistent activation driven by chronic ECM remodeling reactivates developmental transcriptional programs in adult tissues, promoting pathological remodeling rather than regeneration. This transition from adaptive mechanosensing to maladaptive mechanotransduction represents a unifying feature of numerous diseases. In cancer, desmoplastic remodeling sustains YAP/TAZ activation to promote epithelial–mesenchymal transition, metastatic dissemination, immune evasion, and therapeutic resistance. In fibrotic diseases, chronic mechanical stress drives myofibroblast activation and excessive matrix deposition through self-reinforcing positive feedback loops. Likewise, allergic and chronic inflammatory disorders exhibit reciprocal interactions between epithelial dysfunction, immune activation, and ECM remodeling that perpetuate pathological tissue mechanics, while cardiovascular diseases integrate altered hemodynamic forces and ECM stiffening to regulate endothelial dysfunction, vascular remodeling, and cardiac fibrosis5,6.Fig. 1: Integrated regulation of the Hippo signaling pathway by cell adhesion, GPCR, mechanical, and Wnt signaling inputs.Full size imageCell–cell adhesion complexes (α-catenin, Crumbs, and Scribble), G-protein-coupled receptor (GPCR) signaling, extracellular matrix (ECM)-derived mechanical cues, and Wnt signaling converge to regulate Hippo pathway activity. Activation of MST1/2–LATS1/2 promotes phosphorylation-dependent cytoplasmic retention and degradation of YAP/TAZ, whereas suppression of Hippo signaling by ECM stiffness, cytoskeletal tension, or Gαq/11- and Gα12/13-coupled GPCR signaling permits YAP/TAZ nuclear translocation. Nuclear YAP/TAZ interact primarily with TEAD transcription factors, together with additional partners such as SMADs, RUNX, and p73, to induce genes regulating cell proliferation, survival, stemness, migration, and extracellular matrix remodeling. Crosstalk with Wnt/β-catenin signaling further integrates biochemical and mechanical inputs to coordinate tissue homeostasis, regeneration, and disease progression (ANKRD1, ankyrin repeat domain 1; APC, adenomatous polyposis coli; AXL, AXL receptor tyrosine kinase; β-TrCP, beta-transducin repeat-containing protein; BIRC5, baculoviral IAP repeat containing 5; cAMP, cyclic adenosine monophosphate; CK1, casein kinase 1; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; ECM, extracellular matrix; GPCR, G-protein coupled receptor; GSK3, glycogen synthase kinase 3; LATS1/2, large tumor suppressor kinase 1/2; LPA, lysophosphatidic acid; MOB1A/B, MOB kinase activator 1 A/B; MST1/2, mammalian sterile 20-like kinase 1/2; MYC, MYC proto-oncogene; SAV1, Salvador family WW domain-containing protein 1; S1P, sphingosine-1-phosphate; SMADs, small mothers against decapentaplegic proteins; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain transcription factor; YAP, Yes-associated protein).Although substantial progress has been made in understanding Hippo signaling and YAP/TAZ biology, existing reviews have predominantly approached YAP/TAZ from the perspective of intracellular Hippo kinase regulation, transcriptional control, or individual disease contexts. The distinctive perspective of this review is to reverse this direction of analysis by placing the ECM and tissue mechanics at the center of YAP/TAZ biology. Rather than viewing ECM stiffness simply as one of many upstream stimuli of YAP/TAZ, we consider the ECM as a dynamic biomechanical system whose composition, architecture, viscoelasticity, and remodeling determine how mechanical information is generated, transmitted, amplified, and ultimately converted into YAP/TAZ-dependent transcriptional responses. This perspective also emphasizes the reciprocal nature of the relationship: YAP/TAZ activation not only responds to pathological matrix remodeling but also promotes fibroblast activation, ECM deposition, cytoskeletal tension, and matrix remodeling, thereby establishing self-reinforcing feedback loops that can stabilize pathological tissue states. Thus, examining YAP/TAZ through the ECM provides a different understanding of disease in which tissue mechanics are not merely upstream signals but dynamic determinants of cell-state transitions, immune regulation, metabolic adaptation, stromal remodeling, and therapeutic response. Importantly, this ECM-centered framework allows apparently distinct diseases—including cancer, fibrosis, allergic and chronic inflammatory disorders, and cardiovascular disease—to be interpreted through a shared sequence of mechanical perturbation, mechanosensing, YAP/TAZ activation, and tissue-level remodeling, while also accounting for tissue- and cell-specific differences in the downstream response. In this review, we therefore integrate the ECM–integrin–focal adhesion–cytoskeleton–nucleus–YAP/TAZ axis with inflammatory, metabolic, immune, and growth factor signaling networks and examine how this integrated system contributes to disease progression. We further extend this framework to therapeutic strategies that target not only YAP/TAZ–TEAD activity but also pathological ECM remodeling, focal adhesion signaling, cytoskeletal tension, biomaterial properties, and the biomechanical characteristics of individual tissues. By connecting molecular YAP/TAZ signaling with the physical organization of tissues, this review proposes the ECM–mechanotransduction–YAP/TAZ continuum as a framework for understanding disease mechanisms and for developing biomarker-guided precision mechanomedicine.The central premise of this review is that YAP/TAZ should be understood not only as transcriptional effectors of Hippo signaling but as dynamic interpreters of tissue mechanical state. From this perspective, the relevant biological unit extends beyond the YAP/TAZ molecule or the Hippo kinase cascade to encompass the ECM, integrin–focal adhesion complexes, actomyosin cytoskeleton, nuclear architecture, and the reciprocal remodeling of the tissue itself. This broader unit explains why similar YAP/TAZ activation states can produce different outcomes depending on matrix architecture, cellular composition, tissue context, and the duration of mechanical stimulation. It also identifies a clinically relevant distinction between treating YAP/TAZ activity as an intracellular abnormality and correcting the pathological mechanical environment that sustains its activation. The latter perspective provides the conceptual basis for ECM normalization, mechanotherapeutics, biomaterial engineering, spatial mechanophenotyping, and biomarker-guided intervention discussed later in this review.Molecular mechanisms of ECM-driven YAP/TAZ activationECM-driven activation of YAP/TAZ is orchestrated through a highly interconnected mechanotransductive network integrating biomechanical cues, cytoskeletal dynamics, focal adhesion signaling, and nuclear mechanosensing. Mechanical properties of the ECM, including stiffness, viscoelasticity, fiber organization, and topographical architecture, critically determine cellular responses to the extracellular microenvironment. Physiological tissues maintain tightly regulated mechanical profiles that preserve tissue homeostasis; however, pathological remodeling characterized by excessive collagen deposition, fibronectin accumulation, matrix crosslinking, and altered tissue elasticity generates mechanically rigid microenvironments that promote aberrant mechanotransduction7. Increased ECM stiffness is a hallmark of numerous pathological conditions including desmoplastic tumors, fibrotic disorders, allergic airway remodeling, and cardiovascular sclerosis. These biomechanical alterations strongly influence focal adhesion assembly, cytoskeletal organization, nuclear deformation, and transcriptional activity, thereby positioning ECM mechanics as major upstream regulators of YAP/TAZ signaling (Fig. 2). Cells sense mechanical properties of the ECM primarily through integrin-mediated adhesion complexes that physically connect extracellular ligands to the intracellular actin cytoskeleton. Integrin engagement with matrix proteins such as collagen, fibronectin, laminin, and vitronectin induces conformational activation and clustering of integrin heterodimers, resulting in the formation of focal adhesions composed of FAK, Src family kinases, talin, vinculin, paxillin, kindlins, and multiple cytoskeletal adaptor proteins. Mechanical loading and matrix rigidity promote focal adhesion maturation and FAK autophosphorylation, facilitating recruitment of Src kinases and activation of downstream signaling pathways including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and Rho GTPase signaling cascades8. These pathways collectively amplify cytoskeletal tension and regulate YAP/TAZ through both modulation of Hippo kinase activity and mechanical control of cytoskeletal and nuclear states, thereby linking extracellular force transmission to YAP/TAZ localization and transcriptional activity.Fig. 2: Canonical ECM-driven mechanotransduction pathway regulating Hippo–YAP/TAZ signaling.Full size imageA Hippo pathway OFF. Mechanical cues generated by ECM stiffness, stretching, and shear stress are sensed through integrins, focal adhesions, the actin cytoskeleton, and associated RhoA–ROCK signaling, resulting in increased cytoskeletal tension and inhibition of Hippo signaling. Unphosphorylated YAP/TAZ can therefore translocate from the cytoplasm to the nucleus. B Hippo pathway ON. Under low mechanical stress or increased cell–cell contact, MST1/2–LATS1/2 signaling phosphorylates YAP/TAZ, promoting 14-3-3-mediated cytoplasmic retention and SCFβTrCP-dependent degradation. The figure additionally illustrates (I) mechanical cues and cellular sensors, (II) cytoskeletal mechanotransduction through Rho GTPases, ROCK, F-actin polymerization, and actomyosin contractility, (III) nuclear YAP/TAZ–TEAD-mediated transcription, and (IV) integration of ECM mechanics with Hippo pathway activity and downstream cellular outcomes. Active nuclear YAP/TAZ regulate genes involved in proliferation, survival, epithelial–mesenchymal transition, stemness, and tissue remodeling (ANKRD1, ankyrin repeat domain 1; CCND1, cyclin D1; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; FAK, focal adhesion kinase; F-actin, filamentous actin; LATS1/2, large tumor suppressor kinase 1/2; MLCP, myosin light chain phosphatase; MOB1, MOB kinase activator 1; MST1/2, mammalian sterile 20-like kinase 1/2; MYC, MYC proto-oncogene; MYH9/10/11, myosin heavy chain 9/10/11; PC1, polycystin-1; PC2, polycystin-2; ROCK, Rho-associated coiled-coil-containing protein kinase; SAV1, Salvador family WW domain-containing protein 1; SCFβTrCP, Skp1-Cullin-F-box beta-transducin repeat-containing protein ubiquitin ligase complex; Src, proto-oncogene tyrosine-protein kinase Src; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain transcription factor; YAP, Yes-associated protein).Among the major downstream effectors of focal adhesion signaling, Rho family GTPases function as central regulators of cytoskeletal remodeling and intracellular tension generation. Activation of RhoA stimulates Rho-associated coiled-coil containing protein kinase (ROCK), which enhances actomyosin contractility through phosphorylation of myosin light chain and stabilization of actin stress fibers. Increased actomyosin tension enables cells to generate traction forces against the ECM and reinforces focal adhesion integrity, creating a self-amplifying feedback loop between matrix stiffness and cytoskeletal mechanics. Cytoskeletal tension is essential for YAP/TAZ activation, as disruption of actin polymerization, ROCK signaling, or myosin II activity markedly impairs nuclear localization of YAP/TAZ even under stiff ECM conditions. In contrast, soft matrices and reduced cytoskeletal tension generally favor Hippo-mediated phosphorylation and cytoplasmic retention of YAP/TAZ, while the effects of cytoskeletal mechanics on YAP/TAZ can also involve mechanisms that are not fully explained by LATS1/2 activity9. Beyond matrix elasticity, ECM viscoelasticity and structural organization further modulate mechanotransductive signaling. Biological tissues exhibit time-dependent mechanical behaviors characterized by stress relaxation and dynamic deformation under applied force. Cells can distinguish matrices with similar stiffness but differing viscoelastic properties, indicating that dynamic force dissipation substantially influences mechanosensing10. Fast-relaxing matrices facilitate cellular spreading, actin polymerization, and YAP/TAZ activation by allowing efficient force transmission and cytoskeletal remodeling, whereas highly viscous matrices restrict intracellular tension generation. Matrix architecture, including collagen fiber alignment, porosity, dimensionality, and topographical organization, also shapes mechanotransduction by regulating traction force orientation, focal adhesion distribution, and spatial confinement. Aligned collagen networks promote directional migration and persistent YAP/TAZ activation through anisotropic mechanical tension, particularly within tumor and fibrotic microenvironments. In three-dimensional matrices, mechanical confinement and altered force distribution additionally influence nuclear deformation and chromatin accessibility, generating transcriptional responses distinct from conventional two-dimensional culture systems11.Mechanical signaling initiated at focal adhesions is transmitted to the nucleus through the actin cytoskeleton and linker of nucleoskeleton and cytoskeleton (LINC) complexes, providing a mechanotransductive route that is distinct from canonical Hippo kinase regulation. Cytoskeletal tension induces nuclear deformation and changes nuclear envelope mechanics, which can influence nuclear pore permeability and the trafficking of mechanosensitive transcriptional regulators, including YAP/TAZ. In parallel, mechanical deformation can alter chromatin organization, accessibility, and epigenetic state, thereby modifying the transcriptional response to YAP/TAZ activity. Thus, nuclear mechanotransduction represents an additional level of mechanical control in which force can influence YAP/TAZ nuclear localization and transcriptional output without being interpreted solely through MST1/2–LATS1/2 signaling12. Mechanical regulation of chromatin architecture additionally influences histone modifications, epigenetic remodeling, and spatial genome organization, enabling persistent transcriptional reprogramming in response to chronic biomechanical stress. The Hippo pathway functions as a central integrative signaling hub coordinating ECM-derived mechanical signals with inflammatory, metabolic, and growth factor-mediated pathways. Canonically, MST1/2 and LATS1/2 kinases negatively regulate YAP/TAZ through inhibitory phosphorylation, cytoplasmic sequestration, and degradation. Mechanical signals can modulate this pathway, but ECM-driven YAP/TAZ activation also involves parallel mechanotransductive processes, including integrin–FAK–SRC signaling, RhoA–ROCK-dependent actomyosin tension, nuclear deformation, and mechanosensitive changes in nuclear pore and chromatin states. These mechanisms are interconnected rather than strictly hierarchical, allowing mechanical inputs to regulate YAP/TAZ localization and transcriptional activity through both Hippo-dependent and Hippo-independent processes. Mechanosensitive ion channels such as Piezo1 further contribute to YAP/TAZ activation through calcium-dependent signaling pathways that regulate cytoskeletal dynamics and focal adhesion maturation13. Crosstalk between Hippo signaling and TGF-β, Wnt/β-catenin, epidermal growth factor receptor (EGFR), PI3K/AKT, and MAPK pathways amplifies profibrotic, proliferative, and inflammatory responses during pathological remodeling. YAP/TAZ also interact extensively with NF-κB, JAK/STAT, and hypoxia-inducible factor-1α (HIF-1α) signaling networks, thereby integrating biomechanical stress with immune and metabolic adaptation.Persistent activation of ECM-driven YAP/TAZ signaling contributes substantially to disease progression across cancer, fibrosis, inflammatory disorders, and cardiovascular pathology. In solid tumors, desmoplastic ECM remodeling generates mechanically rigid microenvironments that sustain focal adhesion signaling, actomyosin contractility, and YAP/TAZ activation, thereby promoting tumor proliferation, epithelial–mesenchymal transition, metastasis, immune evasion, and therapeutic resistance. Cancer-associated fibroblasts reinforce this process through excessive matrix deposition and lysyl oxidase-mediated collagen crosslinking, creating feed-forward loops of tissue stiffening and mechanotransduction. In fibrotic diseases, chronic activation of RhoA-dependent cytoskeletal tension and YAP/TAZ signaling drives myofibroblast differentiation and excessive ECM accumulation. Similarly, in allergic and chronic inflammatory diseases, pathological ECM remodeling alters tissue compliance and promotes sustained inflammatory activation through mechanosensitive immune signaling pathways. In cardiovascular tissues, disturbed shear stress primarily regulates endothelial mechanotransduction, whereas vascular stiffening and pathological ECM remodeling promote YAP/TAZ activation in vascular smooth muscle cells and fibroblasts, together contributing to vascular inflammation and maladaptive cardiac remodeling14. Figure 2 summarizes the core ECM–mechanotransduction–YAP/TAZ framework; the following disease-specific sections therefore focus on how this conserved mechanobiological axis is modified by tissue-specific cellular, inflammatory, metabolic, and hemodynamic contexts.Immunomodulatory functions of YAP/TAZ in mechanobiologyYAP/TAZ contribute to immune regulation through mechanisms that differ substantially in the strength of direct evidence among immune cell populations. In some settings, experimental manipulation of YAP/TAZ has directly demonstrated effects on immune-cell differentiation, activation, cytokine production, or function; in others, the available evidence primarily shows that immune cells respond to altered ECM stiffness, architecture, or mechanical forces, without establishing YAP/TAZ as the principal intracellular mediator. This distinction is particularly important because mechanosensitive immune responses can involve integrins, the actomyosin cytoskeleton, ion channels, inflammatory signaling, and other pathways in addition to Hippo–YAP/TAZ signaling. Accordingly, the following discussion distinguishes established cell-intrinsic YAP/TAZ functions from broader immune responses to mechanically altered tissue environments15. Macrophages are among the immune populations for which mechanical regulation and YAP/TAZ-associated inflammatory responses have been most closely linked. Stiff or mechanically altered ECM can promote macrophage inflammatory and profibrotic phenotypes, accompanied by changes in cytokine production and stromal remodeling. However, these observations do not necessarily establish YAP/TAZ as the sole or dominant mediator of the macrophage response, because integrin signaling, cytoskeletal tension, and inflammatory pathways can independently contribute to mechanosensitive macrophage activation. Where YAP/TAZ activity has been experimentally manipulated, it provides stronger evidence for a cell-intrinsic regulatory role, whereas studies based primarily on matrix stiffness should be interpreted as evidence of macrophage mechanosensitivity rather than direct proof of YAP/TAZ dependence (Fig. 3). These responses are further amplified through extensive crosstalk with inflammatory signaling networks. Dendritic cells also respond to altered ECM mechanics through cytoskeletal remodeling and changes in antigen-presenting and T-cell-priming functions; however, the extent to which these responses are directly mediated by YAP/TAZ remains less clearly established than in settings where YAP/TAZ are experimentally manipulated. Evidence for neutrophils is currently more consistent with a broader mechanosensitivity phenotype than with a clearly established cell-intrinsic YAP/TAZ mechanism. Mechanical properties of the tissue can influence neutrophil adhesion, migration, deformation, and inflammatory activation, but direct evidence linking these responses specifically to YAP/TAZ remains limited16.Fig. 3: YAP/TAZ-mediated mechanoinflammatory crosstalk during fibrosis.Full size imageECM stiffening activates YAP/TAZ in immune and stromal cells, promoting inflammatory cytokine production, fibroblast activation, and myofibroblast differentiation. These processes enhance ECM deposition, creating a feed-forward loop that perpetuates tissue stiffening, chronic inflammation, and progressive fibrosis (ECM, extracellular matrix; IL-1β, interleukin-1 beta; IL-6, interleukin-6; M1, classically activated macrophage phenotype; M2, alternatively activated macrophage phenotype; TAZ, transcriptional coactivator with PDZ-binding motif; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; YAP, Yes-associated protein).T lymphocytes are highly mechanosensitive, and ECM stiffness, matrix architecture, integrin signaling, actomyosin contractility, and immune-synapse forces can influence T-cell receptor signaling, migration, differentiation, and effector function. These findings primarily establish that T cells respond to tissue mechanics rather than demonstrating that YAP/TAZ mediate all such responses. More direct evidence supports a specific role for TAZ in T-cell lineage programming, particularly in promoting T helper 17 (Th17) differentiation, whereas YAP appears to exert more context-dependent effects on T-cell proliferation, survival, and immune tolerance17. This distinction illustrates that YAP and TAZ should not be considered functionally interchangeable despite their overlapping mechanosensitive regulation. Thus, T-cell mechanosensitivity and TAZ/YAP-dependent transcription should be considered related but not synonymous phenomena. Regulatory T-cell stability and suppressive function are additionally influenced by mechanosensitive signaling pathways within chronically remodeled tissues. Cytotoxic CD8 + T cells rely on dynamic cytoskeletal remodeling to migrate through dense ECMs; however, pathological ECM stiffening and desmoplastic remodeling frequently impair immune infiltration and promote immune exhaustion within tumor microenvironments. B lymphocytes and humoral immune responses are also influenced by force-dependent receptor signaling and cytoskeletal dynamics, although the mechanistic role of YAP/TAZ in B-cell biology remains less well defined18.A major consequence of pathological mechanotransduction is the development of chronic inflammatory remodeling and fibrosis. Fibrotic tissues are characterized by excessive deposition of collagen, fibronectin, and matricellular proteins that increase tissue stiffness and perpetuate mechanical stress signaling. Activated fibroblasts and myofibroblasts exposed to rigid ECM environments exhibit persistent YAP/TAZ activation driven by integrin signaling, focal adhesion maturation, and RhoA-mediated cytoskeletal tension. Once activated, YAP/TAZ cooperate with TEAD transcription factors and profibrotic mediators to induce ECM synthesis, myofibroblast differentiation, and tissue contraction. Mechanical activation of latent TGF-β complexes further amplifies this process, as YAP/TAZ interact with SMAD transcription factors to promote expression of collagen, connective tissue growth factor, and α-smooth muscle actin. These interactions perpetuate progressive fibrotic remodeling through sustained mechanotransductive activation. Inflammatory remodeling is additionally sustained through reciprocal interactions between immune cells and stromal cells within mechanically abnormal microenvironments19. Macrophages exposed to stiffened matrices secrete profibrotic cytokines and growth factors that promote fibroblast activation and ECM accumulation, while activated fibroblasts further enhance tissue rigidity through collagen deposition and lysyl oxidase-mediated matrix crosslinking. Epithelial and endothelial cells also contribute substantially to inflammatory remodeling through YAP/TAZ-dependent regulation of barrier integrity, cytokine secretion, angiogenesis, and epithelial–mesenchymal or endothelial-to-mesenchymal transition. In allergic diseases such as asthma and atopic dermatitis, chronic type 2 inflammatory signaling cooperates with ECM stiffening to promote epithelial dysfunction, fibroblast activation, airway remodeling, and persistent eosinophilic inflammation. Similar mechanobiological processes are observed in pulmonary fibrosis, inflammatory bowel disease, systemic sclerosis, and cardiovascular fibrosis, highlighting the broad role of ECM-driven YAP/TAZ signaling in chronic inflammatory disease progression20.YAP/TAZ signaling is extensively interconnected with cytokine-mediated inflammatory pathways that regulate immune activation and tissue remodeling. Among these, TGF-β signaling represents one of the most critical profibrotic pathways interacting with mechanotransduction. Mechanical stress facilitates integrin-mediated activation of latent TGF-β, while YAP/TAZ cooperate with SMAD proteins to amplify fibrotic transcriptional programs. YAP/TAZ also interact with NF-κB-dependent transcriptional programs to enhance expression of inflammatory cytokines and chemokines involved in leukocyte recruitment and chronic inflammation. IL-6/STAT3 signaling can cooperate with YAP/TAZ-dependent transcriptional programs to promote inflammatory activation, fibroblast proliferation, angiogenesis, and tumor progression within mechanically stiffened tissues. In allergic disease, YAP/TAZ modulate epithelial responses to IL-4, IL-13, IL-25, and IL-33, thereby influencing type 2 inflammation and tissue remodeling21. Hypoxia-induced HIF-1α signaling can cooperate with YAP/TAZ-dependent transcriptional programs to promote inflammatory activation, metabolic adaptation, and pathological remodeling in mechanically abnormal tissues. Emerging evidence further demonstrates that YAP/TAZ-mediated immunoregulation is closely linked to cellular metabolic adaptation. Mechanical activation of YAP/TAZ enhances glycolysis, glutamine metabolism, lipid synthesis, and mitochondrial remodeling required to sustain inflammatory activation, fibroblast proliferation, and immune cell function under conditions of chronic mechanical stress. Cytokine signaling pathways reciprocally influence these metabolic programs, establishing integrated mechano-immunometabolic networks that support persistence of activated stromal and immune cell phenotypes within chronically remodeled tissues22. Overall, the evidence supports a graded model of immune mechanoregulation rather than a uniform YAP/TAZ-dependent mechanism across immune populations. Direct cell-intrinsic roles for YAP/TAZ are better supported in selected T-cell and macrophage contexts, whereas evidence in dendritic cells and particularly neutrophils and B cells more often demonstrates responses to altered mechanical environments without definitively establishing YAP/TAZ as the causal mediator. Accordingly, ECM mechanics should be viewed as a broader upstream determinant of immune behavior, with YAP/TAZ representing one important—but context-dependent—mechanotransductive pathway within this network.ECM–YAP/TAZ signaling in human diseaseTumor microenvironment, immune evasion, and metastasisAberrant ECM-driven YAP/TAZ signaling is a major determinant of tumor progression, but its disease-specific significance lies in the ability of YAP/TAZ to coordinate tumor-cell plasticity with stromal remodeling, immune exclusion, metastatic adaptation, and therapeutic resistance (Fig. 4). Unlike the general mechanotransductive pathway described in Section 2, the tumor microenvironment creates a spatially heterogeneous mechanical niche in which malignant cells, cancer-associated fibroblasts, endothelial cells, and immune populations reciprocally reinforce YAP/TAZ-dependent signaling. In tumor cells, sustained YAP/TAZ activity promotes epithelial–mesenchymal transition, stemness, survival, metabolic adaptation, and invasive behavior. In stromal and vascular compartments, YAP/TAZ additionally regulate desmoplastic remodeling, angiogenesis, and immune accessibility, thereby converting local mechanical abnormalities into tissue-level programs that favor tumor persistence and dissemination5. In tumor cells, the major consequence of sustained YAP/TAZ activity is phenotypic plasticity, characterized by enhanced stemness, epithelial–mesenchymal transition, metabolic adaptation, survival, and invasive capacity. YAP/TAZ also induce matrix metalloproteinases, integrins, and motility-associated genes, facilitating tumor-cell movement through mechanically heterogeneous and confined tissues23. Cancer-associated fibroblasts represent major orchestrators of pathological ECM remodeling within the tumor microenvironment and are themselves highly dependent on YAP/TAZ-mediated mechanotransduction. Exposure to rigid ECM conditions induces persistent YAP/TAZ activation in fibroblasts, promoting myofibroblast differentiation, contractility, and excessive secretion of collagen, fibronectin, periostin, and connective tissue growth factor. This stromal activation establishes self-reinforcing biomechanical feedback loops in which ECM stiffening continuously amplifies mechanotransductive signaling and desmoplastic remodeling. Tumor-associated ECM remodeling also profoundly influences angiogenesis and vascular dysfunction. YAP/TAZ signaling in endothelial cells regulates vascular sprouting, endothelial permeability, inflammatory activation, and abnormal neovascularization in response to disturbed shear stress and mechanical compression24. These aberrant vascular networks contribute to hypoxia, impaired drug delivery, and metabolic stress within tumors, further stabilizing HIF-1α and reinforcing YAP/TAZ-dependent oncogenic signaling pathways.Fig. 4: Dual role of Hippo–YAP/TAZ signaling in tissue homeostasis and cancer progression.Full size imageA Normal tissue homeostasis and tumor suppression. Cell–cell contact and epithelial polarity activate the Hippo kinase cascade, in which MST1/2 and LATS1/2 phosphorylate YAP/TAZ, promoting 14-3-3-mediated cytoplasmic retention and proteasomal degradation. This restricts nuclear YAP/TAZ activity and maintains epithelial homeostasis, tissue architecture, and cell-size control. B Cancer-associated YAP/TAZ activation and oncogenesis. Rigid ECM, increased integrin signaling, loss of cell–cell contact and polarity, and GPCR signaling suppress Hippo pathway activity, allowing YAP/TAZ nuclear translocation and TEAD-dependent transcription. This promotes aberrant proliferation, apoptosis resistance, cancer stem-cell expansion, invasion and metastasis, and chemoresistance (BCL2, B-cell lymphoma 2; CSC, cancer stem cell; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; ECM, extracellular matrix; F-actin, filamentous actin; GPCR, G-protein coupled receptor; LATS1/2, large tumor suppressor kinase 1/2; MST1/2, mammalian sterile 20-like kinase 1/2; MYC, MYC proto-oncogene; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain transcription factor; YAP, Yes-associated protein).A major consequence of ECM-driven YAP/TAZ activation is the establishment of highly immunosuppressive tumor microenvironments that impair effective antitumor immunity. Desmoplastic ECM remodeling restricts cytotoxic immune infiltration and promotes immune exclusion, while persistent YAP/TAZ activation in tumor and stromal cells promotes expression of immunosuppressive cytokines, chemokines, and immune checkpoint molecules including programmed death-ligand 1 (PD-L1)25. Tumor-associated macrophages exposed to rigid ECM environments acquire immunosuppressive and profibrotic phenotypes characterized by enhanced secretion of TGF-β, IL-10, VEGF, and matrix remodeling enzymes that further support tumor progression and immune exclusion. YAP/TAZ signaling additionally modulates dendritic cell activation, T-cell exhaustion, regulatory T-cell recruitment, and myeloid-derived suppressor cell accumulation through extensive crosstalk with NF-κB, JAK/STAT, and hypoxia-inducible signaling pathways. These interactions collectively generate chronically inflamed yet immunologically dysfunctional tumor niches that promote immune evasion and resistance to immune checkpoint blockade26.Mechanotransductive YAP/TAZ signaling also plays a major role in metastatic colonization and formation of premetastatic niches. Primary tumors remodel distant tissue microenvironments through secretion of cytokines, extracellular vesicles, and ECM remodeling enzymes that promote collagen deposition, fibroblast activation, and recruitment of suppressive immune populations prior to metastatic dissemination. Elevated ECM stiffness within metastatic niches facilitates survival and outgrowth of disseminated tumor cells by sustaining YAP/TAZ-dependent stemness and survival programs. In addition, mechanical adaptation through YAP/TAZ signaling enables tumor cells to survive shear stress during intravasation and circulation, as well as mechanical confinement during extravasation into distant tissues27. Persistent YAP/TAZ activation has been strongly associated with resistance to chemotherapy, targeted therapy, radiotherapy, and immunotherapy through induction of antiapoptotic signaling, metabolic plasticity, epithelial–mesenchymal transition, and cancer stem cell phenotypes. Representative experimental models have demonstrated these mechanisms in vivo. For example, genetically engineered mouse models of pancreatic ductal adenocarcinoma and breast cancer show that collagen-rich desmoplastic remodeling promotes persistent YAP/TAZ activation, immune exclusion, and resistance to immune checkpoint blockade, whereas pharmacological disruption of mechanotransductive signaling improves cytotoxic T-cell infiltration and therapeutic responsiveness28,29.Allergic and chronic inflammatory diseasesECM-driven YAP/TAZ signaling contributes to allergic and chronic inflammatory diseases primarily by linking epithelial dysfunction with immune activation and stromal remodeling (Fig. 5). The distinctive feature of these disorders is the close coupling between mechanotransduction and cytokine-driven inflammation: YAP/TAZ activity can modify epithelial barrier integrity and inflammatory mediator production, while cytokine signaling simultaneously promotes fibroblast activation and pathological ECM remodeling. This reciprocal epithelial–immune–stromal interaction is particularly prominent in type 2 inflammatory diseases, where IL-4, IL-5, IL-13, IL-25, IL-33, and thymic stromal lymphopoietin cooperate with YAP/TAZ-dependent programs to sustain tissue remodeling30. In allergic airway diseases such as asthma, chronic type 2 inflammatory signaling driven by IL-4, IL-5, IL-13, IL-25, IL-33, and thymic stromal lymphopoietin cooperates with ECM stiffening to promote airway wall remodeling, goblet cell hyperplasia, mucus hypersecretion, subepithelial fibrosis, and smooth muscle hypertrophy. Mechanical activation of YAP/TAZ within airway epithelial cells can alter epithelial barrier function and inflammatory mediator production, while YAP/TAZ-dependent fibroblast activation promotes excessive collagen deposition and airway stiffening. Experimental models support a role for the combined YAP/TAZ axis in regulating airway epithelial fate and remodeling, although the relative contribution of each paralog may differ between epithelial and stromal compartments31,32.Fig. 5: Hippo–YAP/TAZ signaling in allergic diseases.Full size imageA Overview of Hippo–YAP/TAZ activity in normal and allergic contexts. Under normal homeostasis, active Hippo signaling promotes YAP/TAZ phosphorylation and cytoplasmic sequestration, supporting epithelial barrier integrity, adaptive repair, and balanced immune responses. In allergic tissues, mechanical stress, reduced cell–cell contact, and epithelial barrier disruption favor YAP/TAZ nuclear translocation and TEAD-dependent transcription, contributing to epithelial dysfunction, pathological remodeling, and type 2 inflammation. B Tissue-specific mechanisms and clinical manifestations. In asthma, airway epithelial YAP/TAZ activation is associated with tight-junction disruption and production of alarmins and cytokines, while YAP/TAZ-associated immune and stromal responses contribute to airway wall remodeling, mast-cell and eosinophil activation, mucus hypersecretion, airway hyperresponsiveness, and chronic fibrosis. In atopic dermatitis, mechanical stress and epidermal barrier disruption promote keratinocyte YAP/TAZ activation, altered barrier-protein and alarmin expression, dermal mast-cell activation, cytokine production, and Th2 differentiation, contributing to pruritus, erythema, lichenification, and susceptibility to infection (AD, atopic dermatitis; CCL2, C-C motif chemokine ligand 2; CLDN1, claudin-1; IL-4, interleukin-4; IL-13, interleukin-13; IL-25, interleukin-25; IL-33, interleukin-33; LATS1/2, large tumor suppressor kinase 1/2; MST1/2, mammalian sterile 20-like kinase 1/2; OCLN, occludin; TEAD, TEA domain transcription factor; TSLP, thymic stromal lymphopoietin; VEGFA, vascular endothelial growth factor A; TAZ, transcriptional coactivator with PDZ-binding motif; Th2, T helper 2; YAP, Yes-associated protein).Similar mechanobiological processes contribute to chronic rhinosinusitis and eosinophilic esophagitis, where persistent inflammatory injury induces fibrotic remodeling and altered tissue compliance associated with sustained YAP/TAZ activation33. In atopic dermatitis, chronic cutaneous inflammation and barrier dysfunction are accompanied by aberrant ECM remodeling and altered mechanical properties that influence keratinocyte proliferation, fibroblast activation, and inflammatory immune cell recruitment through mechanosensitive signaling pathways. YAP/TAZ activation in keratinocytes has been associated with impaired epidermal differentiation, enhanced inflammatory cytokine production, and dysregulated tissue repair responses that contribute to chronic skin inflammation and lichenification34. Beyond allergic diseases, ECM-driven YAP/TAZ signaling also contributes substantially to chronic inflammatory disorders including inflammatory bowel disease, rheumatoid arthritis, systemic sclerosis, and pulmonary fibrosis, where persistent mechanical stress and inflammatory signaling cooperate to sustain fibroblast activation, epithelial dysfunction, angiogenesis, and immune dysregulation. Multiple inflammatory cytokine pathways extensively cooperate with YAP/TAZ-mediated mechanotransduction, amplifying chronic inflammatory responses and tissue remodeling. Macrophages and dendritic cells exposed to mechanically rigid microenvironments acquire persistent inflammatory phenotypes characterized by enhanced cytokine secretion and profibrotic signaling, while altered ECM architecture influences T-cell migration, polarization, and immune tolerance. Progressive ECM accumulation additionally generates hypoxic microenvironments that stabilize HIF-1α and reinforce inflammatory and metabolic adaptation through crosstalk with YAP/TAZ signaling35.Fibrotic disorders and tissue remodelingThe defining feature of YAP/TAZ signaling in fibrosis is its ability to convert a normally transient wound-healing response into a self-sustaining myofibroblast–ECM feedback loop. Following tissue injury, activation of the YAP/TAZ mechanotransductive axis supports fibroblast proliferation and repair, whereas persistent activation promotes myofibroblast differentiation, tissue contraction, and excessive ECM production. Although both YAP and TAZ participate in this profibrotic program, their relative contributions may vary according to tissue and cellular context; therefore, evidence for one paralog should not automatically be extrapolated to the other. YAP/TAZ cooperate with TEAD and profibrotic transcriptional regulators to increase expression of collagen, connective tissue growth factor, fibronectin, α-smooth muscle actin, and ECM-remodeling enzymes. The resulting matrix accumulation and tissue stiffening further sustain YAP/TAZ activity, thereby stabilizing the fibrotic phenotype36,37. TGF-β signaling plays a particularly important role in this process, as mechanical tension facilitates integrin-mediated activation of latent TGF-β complexes, while activated TGF-β/SMAD signaling cooperates with YAP/TAZ at the transcriptional level to amplify profibrotic gene expression and epithelial–mesenchymal transition. These interactions are strongly implicated in pulmonary fibrosis, liver cirrhosis, renal fibrosis, cardiac fibrosis, and systemic sclerosis, where persistent ECM remodeling and chronic inflammatory activation progressively impair organ architecture and function. In idiopathic pulmonary fibrosis, stiffened alveolar microenvironments induce sustained YAP/TAZ activation in epithelial cells and fibroblasts, promoting aberrant epithelial regeneration, fibroblast proliferation, and excessive collagen deposition that disrupt normal alveolar architecture and gas exchange. Similarly, bleomycin-induced pulmonary fibrosis models consistently demonstrate that YAP/TAZ activation precedes myofibroblast expansion and excessive ECM deposition, while genetic deletion or pharmacological inhibition of YAP/TAZ attenuates fibrotic remodeling and preserves lung architecture38.In liver fibrosis and cirrhosis, hepatic stellate cells undergo YAP/TAZ-dependent myofibroblastic transformation in response to mechanical stress and inflammatory signaling, contributing to extensive ECM accumulation and vascular distortion39. Cardiac fibrosis is likewise associated with activation of YAP/TAZ-mediated mechanotransduction pathways in cardiac fibroblasts and endothelial cells exposed to increased hemodynamic stress and myocardial injury, resulting in maladaptive ECM remodeling, impaired electrical conduction, and ventricular dysfunction. Endothelial and epithelial dysfunction further contribute to fibrogenesis through YAP/TAZ-dependent regulation of vascular permeability, inflammatory cytokine production, angiogenesis, and endothelial-to-mesenchymal or epithelial-to-mesenchymal transition. Chronic inflammatory signaling involving NF-κB, JAK/STAT, HIF-1α, and IL-mediated pathways extensively interacts with YAP/TAZ mechanotransduction, reinforcing inflammatory activation and fibroblast persistence within mechanically abnormal tissues. Hypoxia generated by excessive ECM accumulation additionally stabilizes hypoxia-inducible signaling pathways that cooperate with YAP/TAZ to promote metabolic adaptation, angiogenesis, and further ECM remodeling. Immune cells exposed to rigid fibrotic microenvironments also acquire profibrotic phenotypes characterized by enhanced secretion of TGF-β, IL-6, connective tissue growth factor, and matrix remodeling enzymes that amplify tissue fibrosis and inflammatory remodeling40.Cardiovascular mechanobiology and vascular remodelingCardiovascular tissues are continuously exposed to dynamic mechanical forces including shear stress, cyclic stretch, pressure overload, and tensile strain, making mechanotransduction a fundamental regulator of vascular homeostasis and cardiac function. Unlike many other tissues in which ECM stiffness represents the predominant mechanical stimulus, cardiovascular tissues are regulated by two complementary classes of biomechanical signals. Hemodynamic forces—including laminar shear stress, disturbed flow, cyclic stretch, and pressure overload—primarily govern endothelial and cardiomyocyte behavior by sensing blood flow and cardiac contraction. In contrast, progressive ECM remodeling and tissue stiffening develop during chronic cardiovascular disease and predominantly influence fibroblasts, vascular smooth muscle cells, and inflammatory cells. Although both classes of mechanical cues converge on YAP/TAZ signaling, they initiate distinct mechanobiological programs that contribute differently to cardiovascular pathology. Increasing evidence identifies ECM-driven YAP/TAZ signaling as central mediators linking biomechanical stress to endothelial dysfunction, vascular remodeling, inflammation, fibrosis, and cardiovascular disease progression (Fig. 6). These two mechanical environments exert distinct effects according to vascular cell type. Hemodynamic forces are particularly important for endothelial cells, whereas ECM stiffness becomes increasingly influential in vascular smooth muscle cells and fibroblasts during pathological remodeling. In endothelial cells, disturbed shear stress is a particularly important regulator of YAP/TAZ activity, with abnormal flow patterns promoting inflammatory activation, altered permeability, reduced nitric oxide bioavailability, leukocyte adhesion, and pathological angiogenesis. Thus, cardiovascular YAP/TAZ signaling cannot be understood solely through the stiffness-dependent ECM pathway; it integrates flow, cyclic stretch, pressure overload, and tissue stiffness according to the specific cardiovascular cell type and disease context41,42. Disturbed shear stress promotes YAP/TAZ activation, regulating endothelial permeability, inflammatory signaling, nitric oxide bioavailability, leukocyte adhesion, and angiogenic responses, although the relative contribution of YAP versus TAZ may vary according to the specific mechanical and cellular context. Under laminar physiological shear stress, YAP/TAZ activity is generally suppressed, contributing to maintenance of endothelial quiescence and vascular homeostasis; conversely, oscillatory or disturbed flow patterns associated with arterial bifurcations and atherosclerosis promote YAP/TAZ activation and proinflammatory endothelial phenotypes characterized by increased expression of adhesion molecules, cytokines, and chemokines that facilitate leukocyte recruitment and vascular inflammation. YAP/TAZ additionally interact with NF-κB, TGF-β, HIF-1α, and JAK/STAT signaling pathways to amplify inflammatory remodeling and endothelial dysfunction under chronic mechanical stress conditions41.Fig. 6: Hippo–YAP/TAZ signaling in cardiovascular disease.Full size imagePhysiological mechanical forces maintain Hippo pathway activity and vascular homeostasis, whereas pathological ECM stiffening and disturbed shear stress promote YAP/TAZ activation. Persistent signaling contributes to endothelial dysfunction, vascular remodeling, cardiac fibrosis, and heart failure through coordinated regulation of inflammatory and profibrotic transcriptional programs (ANKRD1, ankyrin repeat domain 1; AP-1, activator protein 1; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; ECM, extracellular matrix; GPCR, G-protein coupled receptor; ICAM-1, intercellular adhesion molecule 1; LATS1/2, large tumor suppressor kinase 1/2; LPA, lysophosphatidic acid; MST1/2, mammalian sterile 20-like kinase 1/2; SMAD, small mothers against decapentaplegic protein; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain transcription factor; TGF-β, transforming growth factor-beta; VCAM-1, vascular cell adhesion molecule 1; YAP, Yes-associated protein).Vascular smooth muscle cells are similarly regulated by mechanotransductive YAP/TAZ signaling during vascular remodeling and atherogenesis. Increased ECM stiffness promotes phenotypic switching of vascular smooth muscle cells from contractile to proliferative and migratory states through activation of focal adhesion signaling, cytoskeletal tension, and YAP/TAZ-dependent transcriptional programs. This phenotypic transition contributes to neointimal hyperplasia, ECM remodeling, vascular calcification, and plaque progression in atherosclerosis and restenosis43. Mechanical activation of YAP/TAZ also enhances expression of matrix metalloproteinases, connective tissue growth factor, and profibrotic mediators that further disrupt vascular architecture and compliance. In atherosclerotic lesions, desmoplastic ECM remodeling and chronic inflammatory activation create mechanically rigid microenvironments that sustain YAP/TAZ signaling in endothelial cells, smooth muscle cells, macrophages, and fibroblasts, thereby amplifying vascular inflammation and plaque instability7. Macrophages exposed to stiffened vascular ECM acquire proinflammatory phenotypes characterized by enhanced secretion of IL-1β, tumor necrosis factor-α, and reactive oxygen species, further promoting endothelial injury and fibrotic remodeling. Cardiac remodeling following myocardial injury is also strongly influenced by ECM-driven YAP/TAZ activation. Experimental myocardial infarction and pressure-overload models further illustrate the context-dependent nature of YAP/TAZ biology, in which transient activation supports cardiomyocyte survival and regeneration, whereas sustained activation promotes maladaptive fibrosis, ventricular remodeling, and heart failure progression. Following myocardial infarction or chronic pressure overload, activated cardiac fibroblasts and myofibroblasts deposit excessive collagen and fibronectin that increase myocardial stiffness and impair ventricular compliance44. Mechanical activation of YAP/TAZ in cardiac fibroblasts promotes myofibroblast differentiation, ECM synthesis, and profibrotic cytokine production through extensive crosstalk with TGF-β/SMAD signaling pathways. Persistent mechanotransductive signaling contributes to maladaptive cardiac fibrosis, impaired electrical conduction, ventricular hypertrophy, and progressive heart failure. YAP and TAZ also contribute to cardiomyocyte survival, proliferation, metabolic adaptation, and regenerative responses following injury, although their relative contributions are not necessarily equivalent. In particular, transient YAP activation has been associated with cardiomyocyte regenerative and tissue-repair responses, whereas persistent or dysregulated YAP activity can contribute to pathological hypertrophy and remodeling. The specific contribution of TAZ to these processes appears more context dependent and should not automatically be inferred from evidence obtained for YAP. Endothelial-to-mesenchymal transition and inflammatory immune cell recruitment further amplify myocardial remodeling through interactions between cytokine signaling and ECM-dependent mechanotransduction22.Translational and therapeutic perspectivesUnlike conventional therapeutic approaches that primarily target isolated inflammatory or proliferative pathways, mechanotherapeutics aim to modulate the biomechanical microenvironment itself by targeting ECM remodeling, cytoskeletal tension, focal adhesion signaling, and downstream mechanosensitive transcriptional programs (Table 1). Because pathological ECM remodeling sustains chronic mechanotransductive signaling, therapeutic disruption of YAP/TAZ signaling networks offers the potential to simultaneously suppress fibrosis, inflammation, immune suppression, vascular remodeling, and malignant progression across multiple pathological conditions7,37. However, the extensive physiological roles of YAP/TAZ in tissue regeneration, stem cell maintenance, wound healing, and organ homeostasis necessitate highly selective and context-dependent therapeutic approaches to minimize systemic toxicity and preserve normal tissue repair mechanisms. Because YAP/TAZ regulate epithelial renewal, stem cell maintenance, liver regeneration, and post-injury cardiac repair, prolonged systemic inhibition may delay wound healing, impair tissue regeneration, and disrupt normal tissue homeostasis. Consequently, tissue-specific delivery systems, transient inhibition, or context-dependent modulation are likely to offer more favorable therapeutic windows than sustained systemic blockade.Table 1 Current and Emerging Mechanotherapeutic Strategies Targeting ECM–YAP/TAZ Signaling Across Human DiseaseFull size tableDirect inhibition of YAP/TAZ transcriptional activity represents one of the most actively pursued mechanotherapeutic strategies. YAP/TAZ primarily exert their transcriptional effects through interactions with TEAD transcription factors, making the YAP/TAZ–TEAD complex an attractive pharmacological target. Early studies identified verteporfin as a compound capable of disrupting YAP–TEAD interactions and suppressing YAP/TAZ-dependent transcriptional programs associated with fibrosis, epithelial–mesenchymal transition, stemness, inflammatory remodeling, and tumor progression45. More recently, structural characterization of TEAD transcription factors revealed a conserved palmitate-binding pocket critical for TEAD stability and activity, leading to the development of next-generation TEAD autopalmitoylation inhibitors currently undergoing preclinical and early clinical evaluation. Several TEAD-targeting agents have now advanced into early-phase clinical trials, reflecting increasing pharmaceutical interest in selectively disrupting YAP/TAZ–TEAD transcriptional activity. Representative compounds include IK-93046 and VT398947, which are being evaluated for advanced solid tumors, while additional TEAD inhibitors and related transcriptional modulators continue to enter clinical development. In contrast, most upstream mechanotherapeutic approaches—including LOX inhibition, biomaterial-based modulation, RNA-based YAP/TAZ targeting, and many ECM-normalizing strategies—remain predominantly at the preclinical stage despite encouraging efficacy in experimental models. This distinction underscores both the progress achieved in direct YAP/TAZ targeting and the substantial translational challenges that remain before broader clinical implementation.Additional strategies target upstream mechanotransductive regulators controlling cytoskeletal tension and YAP/TAZ activation48. Pharmacological inhibition of these pathways suppresses focal adhesion maturation, actomyosin contractility, fibroblast activation, ECM deposition, endothelial dysfunction, and immune suppression in multiple experimental models of fibrosis, cardiovascular disease, and cancer. FAK inhibitors additionally demonstrate important immunomodulatory effects by improving cytotoxic T-cell infiltration and reducing desmoplastic remodeling within rigid tumor microenvironments. Therapeutic targeting of pathological ECM remodeling itself has emerged as another major translational strategy. Tissue stiffening and excessive matrix rigidity are driven in part by collagen accumulation, fibronectin deposition, and lysyl oxidase (LOX)-mediated matrix crosslinking that amplify mechanotransductive signaling and sustain chronic YAP/TAZ activation. Inhibition of LOX family enzymes reduces collagen crosslinking, normalizes tissue stiffness, suppresses focal adhesion signaling, and attenuates fibrotic progression in preclinical models of fibrosis and cancer. Additional ECM-normalizing strategies aim to restore tissue biomechanics and suppress persistent mechanotransduction. In oncology, ECM normalization approaches may additionally improve vascular perfusion, reduce hypoxia, enhance drug delivery, and facilitate immune cell infiltration into desmoplastic tumors, thereby improving responsiveness to chemotherapy and immune checkpoint blockade49. Despite promising preclinical efficacy, several ECM-targeting therapies have demonstrated only limited or inconsistent benefit in clinical trials. The therapeutic efficacy of ECM-directed interventions is limited by substantial heterogeneity in matrix composition, stiffness, and remodeling across different tissues, disease stages, and individual patients. Moreover, excessive disruption of the ECM may compromise normal tissue architecture, vascular integrity, and wound healing, while compensatory activation of alternative mechanotransductive and inflammatory pathways can attenuate long-term therapeutic responses. These observations suggest that complete suppression of ECM remodeling is unlikely to be universally beneficial. Instead, strategies aimed at restoring physiological tissue mechanics through selective ECM normalization, combined with biomarker-guided patient selection and rational combination therapies, may provide greater clinical efficacy while minimizing unintended adverse effects.Biomaterial-based interventions have further expanded the therapeutic landscape of mechanobiology by enabling precise control of tissue biomechanics and cellular mechanotransduction. Advances in biomaterials science have facilitated development of tunable hydrogels, nanofibrous scaffolds, decellularized matrices, and synthetic ECM analogs capable of reproducing tissue-specific mechanical and structural properties. These engineered systems regulate integrin signaling, cytoskeletal tension, and YAP/TAZ activation through modulation of matrix stiffness, viscoelasticity, ligand density, and three-dimensional architecture50. Mechanically optimized biomaterials may suppress inflammatory and fibrotic phenotypes, promote regenerative responses, and improve stem cell differentiation and tissue repair in regenerative medicine applications. In cardiovascular tissue engineering and wound healing, biomaterials engineered to mimic physiological tissue compliance support endothelialization, vascular maturation, and epithelial regeneration while limiting pathological fibrosis51. Immunomodulatory biomaterials are also being explored as strategies to reduce chronic inflammatory responses, improve immune cell trafficking, and overcome desmoplastic immune exclusion in cancer. Nanotechnology-based delivery systems and matrix-responsive biomaterials further provide opportunities for tissue-specific delivery of YAP/TAZ inhibitors, antifibrotic agents, cytokine modulators, and RNA-based therapeutics in mechanically abnormal tissues52.Given the extensive crosstalk between mechanotransduction and inflammatory signaling pathways, combination therapies targeting multiple components of the mechanobiological network are increasingly viewed as essential for achieving durable therapeutic responses. TGF-β signaling is a particularly important target because of its central role in fibrosis, immune suppression, epithelial plasticity, and ECM remodeling. Combined inhibition of YAP/TAZ and TGF-β signaling demonstrates synergistic suppression of fibroblast activation, matrix deposition, and inflammatory remodeling in experimental models of fibrosis and cancer. Similar combination approaches involving inhibition of IL-6/STAT3, NF-κB, EGFR, PI3K/AKT, and MAPK pathways may further enhance therapeutic efficacy by simultaneously targeting inflammatory, metabolic, and mechanotransductive signaling networks53. In oncology, combination strategies integrating mechanotransductive inhibitors with programmed death-1 (PD-1)/PD-L1 blockade are particularly promising for overcoming immune exclusion and resistance to immunotherapy within mechanically rigid and desmoplastic tumor microenvironments. Emerging therapies additionally target metabolic adaptation associated with YAP/TAZ activation, including glycolysis, glutamine metabolism, lipid synthesis, and hypoxia-inducible signaling pathways that support persistence of activated fibroblasts, inflammatory immune cells, and tumor cells under chronic mechanical stress54.Although advances in biomaterials and combination therapies have expanded the therapeutic repertoire, successful clinical translation increasingly depends on technologies capable of accurately characterizing tissue biomechanics, identifying responsive patient populations, and monitoring therapeutic efficacy. The integration of AI, spatial omics, and computational mechanobiology has emerged as an important component of precision mechanomedicine, enabling integration of quantitative measurements of tissue stiffness, ECM architecture, collagen organization, YAP/TAZ nuclear localization, and spatial transcriptomic profiles. For example, tissue stiffness measurements and quantitative imaging of ECM architecture or collagen organization could be integrated with YAP/TAZ nuclear localization to identify regions of active mechanotransduction, while spatial transcriptomic profiles could provide information on the accompanying cellular and transcriptional states. Models integrating these features could potentially predict clinically relevant outcomes such as fibrosis progression, metastatic potential, immune exclusion, vascular remodeling, or therapeutic responsiveness, thereby linking tissue biomechanics to patient-level risk stratification and treatment selection55. Integration of spatial multiomic datasets with proteomics, epigenomics, and metabolomics further enables multidimensional analysis of cell–cell communication networks and tissue-specific mechanotransductive programs. AI-assisted computational platforms are increasingly used to characterize biomechanical and spatial features associated with pathological mechanotransduction. Machine learning algorithms can integrate quantitative features such as tissue stiffness, ECM fiber orientation and density, spatial patterns of YAP/TAZ localization, and cell-state information from spatial transcriptomics to identify biomechanical signatures associated with fibrosis severity, metastatic potential, immune exclusion, or therapeutic responsiveness. Computational modeling and finite element simulations can complement these approaches by estimating force transmission, cytoskeletal deformation, and stress distribution across multicellular tissues, thereby providing mechanistic explanations for predicted YAP/TAZ activation patterns56. Organ-on-chip platforms, bioengineered tissue systems, and three-dimensional bioprinting technologies integrated with computational modeling further enable simulation of disease-specific mechanical environments and high-throughput testing of mechanotherapeutic interventions. AI-driven drug discovery approaches are also accelerating development of selective YAP/TAZ inhibitors, biomaterial optimization strategies, and personalized mechanotherapeutic combinations based on tissue-specific biomechanical and molecular characteristics57. Despite these technological advances, several critical barriers continue to limit the clinical translation of precision mechanomedicine. Mechanical heterogeneity within tumors and fibrotic tissues complicates therapeutic targeting and response prediction, while context-dependent functions of YAP/TAZ across different tissues raise concerns regarding systemic toxicity and impaired tissue regeneration. Adaptive resistance mechanisms involving compensatory inflammatory or mechanotransductive pathways may additionally limit the long-term efficacy of monotherapy approaches. Nevertheless, the convergence of mechanobiology, biomaterials science, computational modeling, spatial omics, and precision medicine technologies is establishing a new therapeutic framework centered on the biomechanical regulation of disease. Future clinical implementation will likely require biomarker-guided patient selection. Potential biomarkers include tissue stiffness measured by elastography, ECM remodeling signatures (such as collagen organization or LOX expression), YAP/TAZ nuclear localization, TEAD transcriptional activity, and spatial transcriptomic profiles identifying mechanobiologically active tissue niches. Such biomarkers may help identify patients most likely to benefit from mechanotherapeutic interventions while minimizing unnecessary exposure in individuals whose disease is driven predominantly by non-mechanical pathways. Additional challenges include the lack of standardized biomechanical biomarkers, limited integration of spatial multiomic data into routine clinical workflows, incomplete understanding of tissue-specific mechanotransductive networks, and the absence of validated methods for longitudinal monitoring of YAP/TAZ activity during therapy. Furthermore, much of the mechanobiological evidence for YAP/TAZ has been generated using cells cultured on mechanically controlled two-dimensional substrates or in animal models, each of which captures only selected aspects of human tissue mechanics. Two-dimensional systems provide experimental control over stiffness and cell spreading but incompletely reproduce three-dimensional confinement, cell–cell interactions, ECM architecture, viscoelasticity, and spatial mechanical heterogeneity, whereas animal models provide greater tissue-level complexity but may differ from humans in ECM composition, tissue architecture, immune responses, and disease-associated mechanical environments. These limitations are particularly relevant to an ECM-centered framework because the same YAP/TAZ activation state can produce different cellular outcomes depending on matrix organization, tissue geometry, cellular composition, and the temporal dynamics of mechanical stimulation. Addressing these limitations through standardized biomechanical phenotyping, prospective biomarker validation, and multicenter clinical studies will be essential for the successful implementation of precision mechanomedicine. Collectively, these complementary platforms—from engineered biomaterials and organ-on-chip systems to spatial multiomics and AI-assisted computational modeling—constitute the emerging research framework of precision mechanomedicine, providing a foundation for biomarker-guided patient stratification, rational therapeutic design, and longitudinal monitoring of YAP/TAZ-targeted interventions.Future directions and conclusionsECM-driven YAP/TAZ signaling provides a mechanobiological framework that extends beyond the conventional view of YAP/TAZ as downstream transcriptional effectors of Hippo signaling. The central insight emerging from this ECM-centered perspective is that YAP/TAZ activity reflects the integrated mechanical state of the tissue rather than an isolated intracellular signaling event. ECM composition, fiber architecture, stiffness, viscoelasticity, and remodeling determine the forces experienced by cells, while integrin–focal adhesion signaling, actomyosin contractility, nuclear deformation, and chromatin regulation translate these forces into YAP/TAZ-dependent transcriptional programs. Conversely, activated YAP/TAZ promote stromal activation, ECM deposition, and matrix remodeling, creating positive feedback loops that can stabilize pathological mechanical states. This bidirectional relationship provides a common mechanistic framework linking tumor desmoplasia, fibrosis, chronic inflammatory and allergic remodeling, and cardiovascular tissue stiffening despite their distinct cellular and clinical manifestations. Importantly, this framework also changes the therapeutic perspective: rather than viewing YAP/TAZ inhibition as an isolated molecular intervention, pathological mechanotransduction can be targeted at multiple levels, including ECM normalization, integrin and focal adhesion signaling, cytoskeletal tension, YAP/TAZ–TEAD transcriptional activity, and tissue-specific biomechanical modulation. Thus, the ECM–mechanotransduction–YAP/TAZ continuum represents the principal conceptual contribution of this review and provides a basis for integrating tissue biomechanics with molecular biomarkers, spatial profiling, and precision mechanomedicine. These context-dependent functions present a major challenge for therapeutic development, particularly in distinguishing transient YAP/TAZ activation that supports regeneration and tissue repair from persistent activation that drives pathological remodeling, as indiscriminate inhibition may impair physiological regeneration and tissue homeostasis while suppressing pathological signaling. Emerging technologies including biomaterial engineering, spatial multiomics, computational modeling, and AI are expected to facilitate translation; however, their successful implementation depends on addressing several fundamental biological and translational challenges. Future research should prioritize resolving several critical knowledge gaps, including tissue- and cell type-specific regulation of YAP/TAZ, temporal control of mechanotransduction during disease progression, identification of reliable predictive biomarkers, and development of therapeutic strategies capable of selectively inhibiting pathological YAP/TAZ activity while preserving physiological regeneration and tissue homeostasis. Addressing these challenges will require integrated approaches combining spatial multiomics, single-cell technologies, bioengineered tissue models, and AI-assisted computational analyses to better define context-specific mechanobiological signatures, identify predictive biomarkers, and guide rational therapeutic development. Only after these scientific and translational challenges are addressed can precision mechanotherapeutic strategies be safely and effectively implemented in routine clinical practice. Ultimately, successful clinical translation will depend not only on inhibiting pathological mechanotransduction but also on preserving the physiological functions of YAP/TAZ required for tissue homeostasis, regeneration, and immune regulation.