Mechanobiology‐Driven Metabolic Reprogramming: Integrative Roles of YAP/TAZ Signaling and Extracellular Matrix Dynamics

ABSTRACT

Mechanobiology has emerged as a critical regulator of cellular metabolism, linking physical forces to transcriptional, metabolic, and epigenetic adaptations across multiple organ systems. However, the mechanisms by which extracellular matrix (ECM) dynamics and mechanotransduction pathways coordinate metabolic reprogramming in physiological and pathological conditions remain incompletely understood. This review provides a focused mechanometabolic framework integrating cardiovascular, skeletal, and endocrine systems through the convergence of ECM remodeling, cytoskeletal tension, and force‐dependent signaling pathways. Central to this framework is the YAP/TAZ signaling axis, which functions as a mechanosensitive transcriptional regulator downstream of integrin‐focal adhesion kinase (FAK)‐Src, RhoA/ROCK, actomyosin tension, and Hippo‐dependent and Hippo‐independent signaling networks. These pathways regulate metabolic programs involving glycolysis, mitochondrial function, redox homeostasis, and anabolic biosynthesis through downstream targets including GLUT1, HK2, PFKFB3, and mitochondrial regulatory pathways. The review critically examines how aberrant mechanotransduction contributes to cardiovascular remodeling, endothelial dysfunction, fibrosis, and metabolic disease progression, while also discussing the context‐dependent roles of YAP/TAZ signaling in adaptive versus pathological responses. In skeletal metabolism, the gut‐bone axis is presented as a bidirectional mechanochemical network in which microbiota‐derived metabolites, osteoimmune signaling, and biomechanical loading coordinately regulate bone remodeling and systemic metabolism. Furthermore, the review evaluates emerging evidence linking viscoelasticity, mitochondrial dynamics, and immunometabolism to disease progression and therapeutic responsiveness. Advances in mechanobiomaterials and regenerative strategies are also discussed, emphasizing their ability to modulate cellular energetics and mechanotransduction pathways to restore tissue homeostasis. Finally, current limitations in mechanobiology research, including model heterogeneity, tissue‐specific mechanical responses, and translational barriers, are highlighted. Collectively, this review establishes mechanobiology as a systems‐level regulator of metabolic reprogramming and underscores the therapeutic potential of targeting mechanometabolic pathways in human disease.

Abbreviations

ADP

adenosine diphosphate

AFM

atomic force microscopy

AMPK

AMP‐activated protein kinase

ATP

adenosine triphosphate

BMPs

bone morphogenetic proteins

CHRNA5

cholinergic receptor nicotinic alpha 5 subunit

CSC

cancer stem cells

DRP1

dynamin‐related protein 1

ETC

electron transport chain

FAKs

focal adhesion kinases

FGF23

fibroblast growth factor 23

GH

growth hormone

GLP‐1

glucagon‐like peptides 1

GLP‐2

glucagon‐like peptides 2

GLRA1

glycine receptor alpha 1

GLUT2

glucose transporter

GLUT4

glucose transporter Type 4

GSK‐3β

glycogen synthase kinase‐3β

HDAC7

histone deacetylase 7

IL‐10

interleukin‐10

IL‐1β

interleukin‐1 beta

IL‐6

interleukin‐6

IRS‐1

insulin receptor substrate‐1

MRE

magnetic resonance elastography

ND6

NADH‐dehydrogenase‐6

NRF2

nuclear factor erythroid 2‐related factor 2

OPG

osteoprotegerin

PDX‐1

pancreatic duodenal homeobox‐1

PGC ‐1a

peroxisome proliferator‐activated receptor coactivator‐1α

PTH

parathyroid hormone

RANKL

receptor for receptor activators of nuclear factor kappa‐B ligand

RASD1

dexamethasone‐Induced Ras‐Related Protein 1

ROS

reactive oxygen species

SCFAs

short‐chain fatty acids

SLCO5A1

solute carrier organic anion transporter family member 5A1

T2DM

Type 2 diabetes mellitus

TAZ

transcriptional co‐activator with PDZ‐binding Motif

TNF‐α

tumor necrosis factor‐alpha

YAP

yes‐associated protein

1. Introduction

Mechanical forces are fundamental regulators of cellular physiology and tissue homeostasis, governing processes that extend far beyond structural support to include transcriptional regulation, metabolic adaptation, and disease progression. Traditionally, metabolism and mechanobiology were investigated as largely independent biological processes; however, studies demonstrate that biomechanical cues and metabolic pathways are highly interconnected through dynamic mechanotransduction networks (Vining and Mooney 2017). Cells continuously sense and respond to physical stimuli such as extracellular matrix (ECM) stiffness, shear stress, compression, tensile strain, and viscoelastic forces through coordinated signaling mechanisms involving integrins, focal adhesion complexes, mechanosensitive ion channels, cytoskeletal remodeling, and nuclear deformation (Table 1) (Mierke 2024; Tschumperlin and Lagares 2020). These signals are subsequently converted into biochemical responses that regulate gene expression, mitochondrial function, cellular energetics, and lineage specification (Long et al. 2025). This bidirectional interaction between mechanical forces and metabolism has established mechanobiology as a systems‐level regulator of both physiological adaptation and pathological remodeling.

Table 1.

Mechanotransduction‐mediated regulation of YAP/TAZ signaling and metabolic reprogramming.

Mechanical cue	Upstream sensors/mechanotransducers	Major signaling pathways	YAP/TAZ regulatory mechanism	Major downstream target genes	Metabolic outcome	Disease/physiological context	References
ECM stiffening	Integrins, FAK, Src kinases	Integrin‐FAK‐Src, RhoA/ROCK	Increased actomyosin tension promotes nuclear YAP/TAZ localization independent of Hippo signaling	CTGF, CYR61, GLUT1, HK2	Enhanced glycolysis and anabolic metabolism	Cancer, fibrosis	Discher et al. (2005); Sirio Dupont et al. (2011); Panciera et al. (2017)
Fluid shear stress	PECAM‐1, VE‐cadherin, integrins	AMPK, NF‐κB, YAP/TAZ	Disturbed flow promotes nuclear YAP/TAZ accumulation and inflammatory activation	PFKFB, ICAM‐1, VCAM‐1	Endothelial glycolytic activation and inflammation	Atherosclerosis	Nakajima et al. (2017); K.‐C. Wang et al. (2016)
Matrix viscoelasticity	Cytoskeleton, focal adhesions	RhoA/ROCK, mitochondrial signaling	Cytoskeletal tension regulates YAP/TAZ‐dependent mechanoadaptation	GLS1, PGC‐1α‐associated pathways	Mitochondrial adaptation and glutaminolysis	Fibrosis, pulmonary hypertension	Bertero et al. (2016); Papalazarou et al. (2020); Romani et al. (2021)
Mechanical stretch	Integrins, actomyosin fibers	MAPK, TGF‐β, YAP/TAZ	Stretch‐induced cytoskeletal remodeling enhances TEAD‐dependent transcription	CTGF, collagen‐associated genes	Fibrotic anabolic metabolism	Cardiac remodeling	Byun et al. (2019); Hinz (2015); F. Liu et al. (2015)
Nuclear deformation	LINC complex, nuclear lamina	Cytoskeletal‐nuclear coupling	Nuclear flattening increases chromatin accessibility and YAP/TAZ retention	Proliferative and metabolic transcriptional programs	Metabolic adaptation and mechanosensitive gene activation	Stem cells, cancer	Maurer and Lammerding (2019)
Piezo1 activation	Piezo1 mechanosensitive ion channel	Ca2+ signaling, RhoA/ROCK	Ca2+ influx promotes cytoskeletal remodeling and YAP/TAZ activation	Osteogenic and metabolic regulatory genes	Calcium signaling and metabolic remodeling	Osteogenesis, vascular remodeling	J. Li et al. (2014)
Hippo pathway activation	MST1/2, LATS1/2 kinases	Canonical Hippo signaling	YAP/TAZ phosphorylation induces cytoplasmic retention and degradation	Reduced TEAD‐dependent transcription	Suppressed anabolic metabolism and proliferation	Homeostasis, tumor suppression	Stefano Piccolo et al. (2014)
ECM remodeling and fibrosis	Fibroblasts, integrins	TGF‐β‐SMAD, YAP/TAZ	Persistent YAP/TAZ activation drives fibroblast metabolic reprogramming	COL1A1, CTGF, CYR61	Collagen synthesis and fibrotic metabolism	Pulmonary and liver fibrosis	Hinz (2015); F. Liu et al. (2015)
Substrate elasticity	Focal adhesions, cytoskeleton	YAP/TAZ, Wnt/β‐catenin	Elasticity‐dependent YAP/TAZ activation regulates lineage‐specific transcription	RUNX2, osteogenic regulators	Osteogenic metabolic differentiation	Bone regeneration	Discher et al. (2005); Panciera et al. (2017)
Cytoskeletal contractility	Actin stress fibers, myosin II	RhoA/ROCK, actomyosin signaling	Stress‐fiber tension enhances YAP/TAZ nuclear translocation	Glycolytic and proliferative genes	Aerobic glycolysis and biosynthesis	Cancer metabolism	Enzo et al. (2015)

At the cellular level, mechanotransduction is tightly linked to metabolic reprogramming through force‐sensitive signaling pathways that integrate extracellular mechanical inputs with intracellular bioenergetic responses. Cytoskeletal tension generated through actomyosin contractility alters cellular rheological properties and regulates force transmission across the plasma membrane, cytoskeleton, and nucleus (Murrell et al. 2015; N. Wang 2017). These biomechanical changes influence chromatin organization, transcriptional accessibility, mitochondrial dynamics, and redox balance, thereby coupling physical forces to cellular metabolism (Abdollahiyan et al. 2020; Zha et al. 2025). Central to this mechanometabolic network is the YAP/TAZ signaling axis, which functions as a mechanosensitive transcriptional regulator downstream of integrin‐FAK‐Src signaling, RhoA/ROCK‐mediated cytoskeletal tension, actomyosin remodeling, and Hippo‐dependent and Hippo‐independent pathways (Sirio Dupont et al. 2011; Panciera et al. 2017). Under conditions of matrix stiffening or altered mechanical loading, YAP/TAZ translocates to the nucleus and interacts with TEAD transcription factors to regulate metabolic programs associated with glycolysis, glutaminolysis, mitochondrial adaptation, and anabolic biosynthesis (Cai et al. 2021). Mechanistically, YAP/TAZ activation has been linked to increased expression of glucose transporter‐1 (GLUT1), hexokinase‐2 (HK2), and phosphofructokinase‐2/fructose‐2,6‐bisphosphatase‐3 (PFKFB3), thereby promoting glycolytic flux and metabolic adaptation under mechanical stress conditions (Enzo et al. 2015; K.‐C. Wang et al. 2016). Furthermore, YAP‐dependent activation of glutaminase‐mediated glutaminolysis has been shown to support vascular remodeling and proliferative tissue growth, emphasizing the central role of mechanotransduction in coordinating metabolic reprogramming (Bertero et al. 2016; Cox et al. 2016).

The ECM represents a highly dynamic and mechanically active microenvironment composed of interconnected structural proteins, glycoproteins, and tethered signaling molecules that collectively regulate tissue architecture and cellular behavior (Malandrino et al. 2018; Mierke 2024). Beyond its structural role, the ECM acts as a mechanochemical signaling platform that modulates cell survival, differentiation, migration, proliferation, and metabolism through continuous reciprocal interactions with resident cells. Fibroblasts, endothelial cells, adipocytes, macrophages, stem cells, and epithelial cells actively remodel the ECM while simultaneously responding to changes in matrix stiffness and viscoelasticity (F. Liu et al. 2015; Nawaz et al. 2018; Roy Roy Choudhury et al. 2019; Shen et al. 2020). Alterations in ECM composition and tissue mechanics have been implicated in diverse pathological conditions including fibrosis, cardiovascular disease, metabolic dysfunction, aging, and cancer progression. Importantly, mechanical properties of the ECM can differentially regulate cellular metabolism depending on tissue type, disease stage, and duration of mechanical stimulation, highlighting the context‐dependent nature of mechanobiological responses.

Recent studies further suggest that mechanometabolic regulation represents a conserved biological principle operating across multiple organ systems rather than an isolated phenomenon restricted to specific tissues (S. Dupont 2025; Fabiano et al. 2025). In cardiovascular tissues, disturbed shear stress and vascular stiffening induce endothelial metabolic reprogramming and inflammatory activation through YAP/TAZ‐dependent pathways, contributing to vascular remodeling and atherosclerosis (Ritsvall and Albinsson 2024; K.‐C. Wang et al. 2016). In skeletal biology, mechanical loading integrates with microbiota‐derived metabolites and endocrine signaling to regulate osteogenesis, osteoclast activity, and calcium homeostasis through the gut‐bone axis (Ye et al. 2026). Similarly, in endocrine and metabolic disorders such as Type 2 diabetes mellitus (T2DM), altered ECM stiffness, mitochondrial dysfunction, and epigenetic remodeling collectively impair pancreatic β‐cell function and insulin sensitivity (L. Wu and Coletta 2025). These observations indicate that mechanotransduction not only governs structural adaptation but also orchestrates systemic metabolic homeostasis across physiologically distinct tissues.

Despite substantial progress in mechanobiology research, several critical challenges remain unresolved. The biological consequences of mechanical signaling are highly context dependent and may exert adaptive or pathological effects depending on cellular state, temporal duration, and microenvironmental conditions. For example, YAP/TAZ activation can promote regenerative responses during tissue repair while simultaneously driving fibrosis, tumor progression, or metabolic dysfunction under chronic mechanical stress. Furthermore, many mechanobiological findings rely heavily on two‐dimensional in vitro culture systems that incompletely recapitulate the complex viscoelastic and biochemical properties of native tissues. Differences between in vitro, animal, and human studies continue to limit translational interpretation and therapeutic implementation. Emerging technologies including organ‐on‐chip systems, spatial metabolomics, mechanotranscriptomics, artificial intelligence (AI)‐driven biomechanical modeling, and adaptive biomaterials are expected to substantially improve understanding of mechanometabolic regulation in physiologically relevant environments.

This review critically examines mechanobiology‐driven metabolic reprogramming across cardiovascular, skeletal, and endocrine systems through the integrated roles of ECM dynamics, viscoelasticity, mechanotransduction, and YAP/TAZ signaling. Particular emphasis is placed on how mechanical cues regulate mitochondrial metabolism, glycolytic adaptation, immunometabolism, and tissue remodeling in health and disease. In addition, the review discusses the translational potential of mechanobiomaterials and mechanometabolic therapeutics aimed at restoring tissue homeostasis and metabolic function. By integrating mechanotransduction with metabolism across multiple organ systems, this review highlights mechanobiology as a unifying framework for understanding disease progression and developing next‐generation therapeutic strategies.

1.1. Literature Search Strategy

A comprehensive narrative literature search was performed to identify relevant studies investigating the interplay between mechanobiology, ECM dynamics, mechanotransduction, YAP/TAZ signaling, metabolic reprogramming, and disease progression across cardiovascular, skeletal, endocrine, fibrotic, and regenerative systems. The literature search was primarily conducted using electronic databases including PubMed (https://pubmed.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.com/), and ScienceDirect (https://www.sciencedirect.com/). Articles published predominantly within the last decade (2016–2026) were prioritized to ensure inclusion of recent mechanistic advances, translational developments, and emerging mechanometabolic concepts, although landmark earlier studies of foundational importance were also included where appropriate.

The search strategy incorporated combinations of keywords and Boolean operators including: “mechanobiology,” “mechanotransduction,” “extracellular matrix,” “ECM stiffness,” “YAP/TAZ signaling,” “Hippo pathway,” “metabolic reprogramming,” “mechanometabolism,” “viscoelasticity,” “fibrosis,” “Type 2 diabetes,” “gut‐bone axis,” “cardiovascular remodeling,” “mechanobiomaterials,” “mitochondrial metabolism,” “epigenetic regulation,” and “regenerative medicine.” Additional manual searches of reference lists from relevant reviews and original research articles were also performed to identify potentially relevant studies not captured during the initial database search. Priority was given to peer‐reviewed original research articles, mechanistic studies, translational investigations, and high‐impact review articles that directly addressed mechanotransduction‐mediated metabolic regulation under physiological and pathological conditions. Studies focusing on molecular signaling pathways, ECM remodeling, mechanosensitive transcriptional regulators, mitochondrial adaptation, immunometabolism, tissue viscoelasticity, and biomaterial‐based mechanotherapies were specifically emphasized. Clinical and preclinical studies were included where relevant to support translational perspectives. Articles were screened based on relevance to the central mechanometabolic framework of the review. Studies lacking direct mechanobiological or metabolic relevance, non‐English publications, conference abstracts without full‐text availability, and non‐peer‐reviewed sources were excluded. The final selection of literature was curated to provide an integrative and mechanistically focused overview of how biomechanical forces regulate metabolic adaptation and disease progression across multiple organ systems.

2. Mechanistic Integration of YAP/TAZ Signaling in Mechanobiology‐Driven Metabolic Reprogramming

The YAP/TAZ signaling axis functions as a central mechanotransduction hub integrating extracellular mechanical stimuli with transcriptional, metabolic, and cytoskeletal responses. However, the regulatory mechanisms governing YAP and TAZ activation are highly complex and involve both Hippo‐dependent and Hippo‐independent pathways that vary according to cellular context, ECM architecture, tissue stiffness, and biomechanical loading conditions. Canonically, Hippo‐dependent signaling involves activation of the mammalian sterile 20‐like kinases MST1/2 and large tumor suppressor kinases LATS1/2, which phosphorylate YAP and TAZ, thereby promoting cytoplasmic retention and proteasomal degradation. Under conditions of reduced Hippo kinase activity, unphosphorylated YAP/TAZ translocates into the nucleus where they interact predominantly with TEA domain family (TEAD) transcription factors to regulate gene expression programs associated with proliferation, survival, mechanoadaptation, and metabolic reprogramming (Cai et al. 2021; Dobrokhotov et al. 2018; Jafarinia et al. 2024; Panciera et al. 2017; Stefano Piccolo et al. 2014). Importantly, mechanical regulation of YAP/TAZ frequently occurs independently of canonical Hippo signaling. ECM stiffening, integrin clustering, and focal adhesion maturation activate integrin‐FAK‐Src signaling cascades that subsequently stimulate RhoA/ROCK‐mediated actomyosin contractility and cytoskeletal tension, thereby promoting nuclear localization of YAP/TAZ even in the absence of direct Hippo pathway inhibition (Dobrokhotov et al. 2018; Sirio Dupont et al. 2011). Increased actomyosin tension enhances stress fiber formation and mechanical coupling between the cytoskeleton and nucleus through the linker of nucleoskeleton and cytoskeleton (LINC) complex, resulting in nuclear deformation and altered chromatin accessibility. These biomechanical alterations facilitate YAP/TAZ nuclear accumulation and TEAD‐dependent transcriptional activation of mechanometabolic target genes (Jones et al. 2023; Maurer and Lammerding 2019).

Recent evidence further indicates that YAP and TAZ may exert overlapping yet distinct biological functions. Although both proteins share structural homology and TEAD‐binding capacity, YAP is more frequently associated with proliferative signaling, glycolytic reprogramming, and tissue growth, whereas TAZ demonstrates stronger context‐dependent roles in stem‐cell lineage specification, osteogenesis, and immune regulation (Cunningham and Hansen 2022; Panciera et al. 2017). Differential post‐translational modifications, nuclear retention kinetics, and interactions with transcriptional cofactors may therefore contribute to tissue‐specific mechanotransduction outcomes. Mechanosensitive ion channels also represent important upstream regulators of YAP/TAZ activity (Nam et al. 2026). Piezo1, a mechanically activated calcium‐permeable ion channel, responds to membrane tension, fluid shear stress, and matrix deformation by inducing intracellular Ca²⁺ influx and activation of downstream RhoA/ROCK and cytoskeletal remodeling pathways (J. Li et al. 2014). Piezo1‐mediated mechanotransduction has been implicated in vascular remodeling, osteogenesis, fibrosis, and cancer progression, where it cooperatively regulates YAP/TAZ nuclear localization and metabolic adaptation. Similarly, transient receptor potential (TRP) channels and stretch‐sensitive ion transport systems contribute to force‐dependent regulation of mitochondrial metabolism, reactive oxygen species (ROS) production, and cellular energetics (Y. J. Hu et al. 2025; Zhong et al. 2023).

At the transcriptional level, TEAD‐dependent YAP/TAZ activation regulates several metabolic genes involved in glycolysis, glutaminolysis, mitochondrial adaptation, and anabolic biosynthesis. Mechanically activated YAP/TAZ signaling has been associated with increased expression of GLUT1, HK2, PFKFB3, glutaminase‐1 (GLS1), connective tissue growth factor (CTGF), and cysteine‐rich angiogenic inducer 61 (CYR61), thereby linking biomechanical stress to metabolic reprogramming and ECM remodeling (Bertero et al. 2016; Enzo et al. 2015; Zhao et al. 2023). In endothelial cells, disturbed flow‐induced YAP/TAZ activation promotes inflammatory glycolysis and vascular dysfunction, whereas in fibrotic tissues persistent YAP/TAZ signaling enhances collagen synthesis, fibroblast activation, and anabolic metabolism (Hooglugt et al. 2020; Noguchi et al. 2018). Conversely, transient YAP activation during tissue repair may support regenerative metabolism and cellular survival, highlighting the highly context‐dependent nature of mechanotransduction signaling.

Despite substantial advances, several unresolved questions remain regarding the mechanobiology of YAP/TAZ signaling. The relative contribution of Hippo‐dependent versus Hippo‐independent regulation varies considerably across tissues and disease states, and the molecular determinants governing adaptive versus pathological YAP/TAZ activation remain incompletely understood (Ghosh et al. 2026). In addition, many mechanotransduction studies rely heavily on simplified in vitro systems that inadequately replicate physiological viscoelasticity and multicellular tissue architecture (Cacopardo et al. 2022). Emerging approaches including organ‐on‐chip technologies, mechanotranscriptomics, single‐cell spatial profiling, and adaptive biomaterials are expected to improve understanding of force‐dependent metabolic regulation in physiologically relevant microenvironments.

2.1. Mechanobiology, Tumor Immunometabolism, and Matrix Stiffness‐Induced Metabolic Heterogeneity

Tumor mechanobiology extends far beyond cancer stem‐cell regulation and glioblastoma progression, functioning as a major determinant of tumor immunometabolism, immune evasion, and metabolic heterogeneity within the tumor microenvironment. Tumors are characterized by progressive ECM stiffening, aberrant collagen crosslinking, elevated interstitial pressure, and altered tissue viscoelasticity, all of which profoundly influence cancer cell metabolism and immune‐cell function (Pickup et al. 2014). Increased matrix stiffness activates integrin‐FAK‐Src and RhoA/ROCK signaling pathways, promoting nuclear localization of YAP/TAZ signaling and subsequent transcriptional activation of glycolytic and anabolic metabolic programs (Koo and Guan 2018). Mechanistically, stiff tumor matrices enhance the expression of GLUT1, HK2, PFKFB3, and glutaminase‐associated metabolic pathways, thereby driving aerobic glycolysis, mitochondrial adaptation, and metabolic plasticity that support tumor survival under hypoxic and nutrient‐restricted conditions (Enzo et al. 2015).

Importantly, biomechanical remodeling within tumors also exerts profound effects on antitumor immunity. Increased ECM stiffness and cytoskeletal tension impair T‐cell infiltration, alter macrophage polarization, and promote immunosuppressive microenvironments through YAP/TAZ‐mediated inflammatory signaling and metabolic competition (X. Zhang et al. 2026). Mechanically stressed tumor cells exhibit enhanced lactate production and altered amino acid metabolism, which suppress cytotoxic T‐cell activity and promote the accumulation of regulatory T cells and tumor‐associated macrophages (Jin et al. 2025). In parallel, stiff extracellular matrices induce immune checkpoint expression, including PD‐L1, through YAP/TAZ‐dependent transcriptional regulation, thereby facilitating immune evasion and resistance to immunotherapy (Janse van Rensburg et al. 2018; M. H. Kim et al. 2018). These findings suggest that mechanical signaling directly contributes to tumor immunosuppression by coupling metabolic reprogramming with inflammatory and immune‐regulatory pathways.

Mechanical heterogeneity within tumors further contributes to spatial metabolic diversity and therapeutic resistance. Regions of increased matrix stiffness display elevated glycolytic metabolism, oxidative stress adaptation, and mitochondrial reprogramming compared with softer tumor regions, generating metabolically distinct tumor subpopulations with variable sensitivity to chemotherapy and immunotherapy (Mpekris et al. 2020). Moreover, cancer‐associated fibroblasts mechanically remodel the ECM through collagen deposition and contractility, creating feed‐forward mechanometabolic circuits that sustain fibrosis, angiogenesis, and invasive migration (Belhabib et al. 2021). Mechanosensitive ion channels such as Piezo1 additionally regulate calcium‐dependent metabolic signaling and invasive behavior in response to matrix deformation and compressive stress (Nourse and Pathak 2017). Recent translational studies suggest that targeting tumor mechanics may improve metabolic and immunological therapeutic responses. Strategies aimed at reducing matrix stiffness, inhibiting integrin‐FAK signaling, modulating YAP/TAZ activity, or normalizing tumor biomechanics have demonstrated potential to restore immune‐cell infiltration, reduce glycolytic dependency, and improve responsiveness to immune checkpoint blockade therapies (H.‐S. Kim and Nam 2025; M. Zhang and Zhang 2025). Collectively, these findings establish tumor mechanobiology as a critical regulator of immunometabolic adaptation, metabolic heterogeneity, and therapeutic resistance, highlighting the importance of integrating biomechanics into precision oncology and cancer metabolism research (Figure 1).

Figure 1.

Mechanotransduction‐mediated regulation of cellular metabolism through YAP/TAZ signaling. Diverse mechanical stimuli, including matrix stiffness, fluid shear stress, substrate topography, dynamic strain, and cell–matrix interactions, are sensed through integrin‐associated mechanotransduction pathways involving FAK/Src and RhoA/ROCK signaling. These inputs regulate Hippo pathway activity and YAP/TAZ phosphorylation status, controlling YAP/TAZ nuclear translocation and TEAD‐dependent transcription. The resulting mechanometabolic reprogramming influences mitochondrial function, glycolysis, lipid and amino acid metabolism, and antioxidant responses, thereby linking extracellular mechanical cues to cellular adaptation and disease progression.

3. YAP/TAZ‐Mediated Mechanotransduction in Cardiovascular Disease and Metabolic Regulation

Cardiovascular development is tightly regulated by YAP/TAZ signaling, which governs key processes including cardiac morphogenesis, specification of cardiac progenitor cells, and vascular formation. YAP/TAZ signaling also plays a crucial role in maintaining cardiac homeostasis in adult tissues by regulating endothelial cell function, angiogenesis, and vascular barrier integrity (Islam and Hong 2024; J. Kim et al. 2017). Vascular remodeling is driven by tightly coordinated processes such as cell proliferation, apoptosis, migration, and ECM remodeling (Yu et al. 2020). Importantly, these processes are not solely genetically programmed but are highly sensitive to biomechanical cues, including shear stress, cyclic strain, and matrix stiffness, which dynamically regulate endothelial and vascular smooth muscle cell (VSMC) behavior.

Hemodynamic alterations, oxidative stress, and inflammation can induce pathological vascular remodeling, leading to endothelial dysfunction, aberrant VSMC migration, and ECM degradation, thereby compromising vascular integrity and promoting disease progression (Table 2) (R. Li and Huang 2023). At the molecular level, YAP/TAZ functions as a central mechanosensor that transduces these physical stimuli into transcriptional responses, thereby coupling vascular biomechanics to metabolic regulation and gene expression. When the Hippo signaling pathway is active, YAP/TAZ undergoes phosphorylation, resulting in cytoplasmic sequestration or proteasomal degradation; conversely, pathway inactivation leads to nuclear translocation of YAP/TAZ, where it interacts with TEAD transcription factors to regulate target genes involved in proliferation, survival, and metabolic adaptation (Heng et al. 2020).

Table 2.

Organ‐specific mechanometabolic alterations across physiological systems.

Biological system	Dominant mechanical environment	Major mechanometabolic adaptation	Functional consequence	Disease association	Translational/clinical relevance	References
Cardiovascular system	Hemodynamic shear stress and vascular pressure	Endothelial metabolic reprogramming and oxidative stress adaptation	Vascular remodeling and endothelial dysfunction	Atherosclerosis, hypertension	Vascular mechanotherapy and endothelial‐targeted interventions	Nakajima et al. (2017); K.‐C. Wang et al. (2016)
Pancreatic β‐cells	Pancreatic ECM stiffening and fibrosis	Impaired glucose sensing and insulin secretory metabolism	β‐cell dysfunction and metabolic instability	Type 2 diabetes mellitus	Epigenetic and mechanometabolic therapeutic targeting	Cebola et al. (2015); George et al. (2012)
Bone (gut‐bone axis)	Skeletal loading and biomechanical strain	Osteoimmune and microbiota‐associated calcium metabolism	Bone remodeling and mineral homeostasis	Osteoporosis	Exercise‐mediated bone preservation and microbiota modulation	Lucas et al. (2018); Wei et al. (2025)
Cancer microenvironment	Matrix rigidity and viscoelastic stress	Aerobic glycolysis and anabolic metabolic adaptation	Tumor proliferation, invasion, and metabolic plasticity	Solid tumors	Matrix‐normalization and mechanometabolic cancer therapy	Panciera et al. (2017); Paszek et al. (2005)
Immune system	Cytoskeletal remodeling and cellular tension	Immunometabolic switching between glycolysis and oxidative phosphorylation	Inflammatory activation and immune adaptation	Chronic inflammatory disorders	Immunometabolic modulation	O'Neill et al. (2016)
Fibrotic tissues	Persistent ECM stiffening	Enhanced collagen biosynthesis and fibroblast metabolic activation	Progressive tissue fibrosis	Pulmonary and hepatic fibrosis	Anti‐fibrotic and ECM‐targeted therapy	Hinz (2015); F. Liu et al. (2015)
Skeletal muscle	Mechanical stretch and contractile loading	Mitochondrial biogenesis and fatty acid oxidation	Muscle regeneration and metabolic adaptation	Muscle wasting disorders	Rehabilitation and exercise‐based therapies	Scott (2010)
Cartilage	Compressive mechanical loading	ECM turnover and lipid metabolic adaptation	Chondrocyte survival and cartilage maintenance	Osteoarthritis	Load‐responsive cartilage regeneration strategies	Sirio Dupont et al. (2011)
Liver	Viscoelastic stress and hepatic stiffness	Lipid metabolic dysregulation and oxidative stress	Hepatic remodeling and metabolic dysfunction	NAFLD and liver fibrosis	Mechanodiagnostic and anti‐fibrotic approaches	Romani et al. (2021)
Regenerative tissues	Biomaterial‐guided biomechanical stimulation	Biosynthetic and mitochondrial metabolic enhancement	Tissue regeneration and wound repair	Chronic wounds and tissue injury	Mechanobiomaterial‐based regenerative medicine	X. Lin et al. (2020); Yeh et al. (2021)

YAP/TAZ not only regulates structural remodeling but also orchestrates metabolic reprogramming in cardiovascular cells. In endothelial cells, disturbed flow conditions promote YAP/TAZ activation, which enhances glycolytic flux and inflammatory gene expression, thereby contributing to endothelial dysfunction and atherogenesis (Nakajima et al. 2017; K.‐C. Wang et al. 2016). In contrast, laminar shear stress suppresses YAP/TAZ activity, maintaining endothelial quiescence and metabolic homeostasis. Similarly, in VSMCs, YAP/TAZ activation drives phenotypic switching from a contractile to a synthetic state, characterized by increased proliferation, migration, and metabolic shifts toward glycolysis and biosynthetic pathways (Xie et al. 2012).

Blood vessels are continuously exposed to mechanical forces such as shear stress and pressure fluctuations, which critically influence vascular tone, endothelial function, and cardiac remodeling (Garoffolo and Pesce 2023; Katoh 2023). Reduced coronary wall shear stress has been strongly associated with endothelial dysfunction and the development of nonobstructive coronary artery disease (M. Zhou et al. 2023). Mechanistically, low or oscillatory shear stress induces sustained YAP/TAZ nuclear localization, leading to pro‐inflammatory and pro‐atherogenic transcriptional programs, including activation of NF‐κB signaling and oxidative stress pathways. Dysregulated mechanical forces contribute to the development of cardiovascular diseases such as atherosclerosis, characterized by lipid accumulation, inflammation, and plaque formation in arterial walls (Islam and Hong 2024; H. Li et al. 2010). Beyond endothelial dysfunction, YAP/TAZ signaling also plays a pivotal role in cardiac remodeling following injury. In myocardial infarction, YAP activation has been shown to promote cardiomyocyte proliferation, survival, and metabolic adaptation by enhancing glucose utilization and mitochondrial efficiency (Z. Lin et al. 2015; Xin et al. 2013). However, sustained or aberrant activation may contribute to pathological hypertrophy and fibrosis, highlighting a context‐dependent dual role. Investigating the mechanisms by which endothelial and smooth muscle cells sense and react to mechanical stimuli may yield innovative therapeutic strategies to avoid or mitigate detrimental cardiovascular conditions (Poduri et al. 2017). Collectively, YAP/TAZ signaling emerges as a central integrator of mechanical and metabolic cues in the cardiovascular system, linking ECM mechanics, hemodynamic forces, and cellular energetics to disease progression. Targeting YAP/TAZ‐dependent mechanometabolic pathways thus represents a promising strategy for therapeutic intervention in cardiovascular diseases.

4. Mechanochemical and Microbiota‐Driven Regulation of the Gut‐Bone Axis in Skeletal Metabolism

Skeletal metabolism is a dynamic and tightly regulated process influenced by nutritional status, hormonal signaling, and mechanical stimuli. Traditionally, bone homeostasis has been attributed to endocrine regulators such as parathyroid hormone (PTH), vitamin D, and calcitonin, which coordinate calcium and phosphate balance. However, emerging evidence has expanded this paradigm to include the gastrointestinal system, establishing the gut‐bone axis as a critical regulator of skeletal remodeling. The mechanochemical biology‐dependent gut‐bone axis integrates biomechanical forces, such as those generated during physical activity, with biochemical signals derived from nutrient absorption and gut microbiota (Shi et al. 2026; Wei et al. 2025). Importantly, mechanical loading and substrate stiffness have been shown to modulate osteocyte mechanosensing pathways, including Wnt/β‐catenin and YAP/TAZ signaling, thereby linking physical forces to osteogenic differentiation and metabolic activity (Moharrer 2025; Virdi and Pethe 2021).

Numerous gut‐derived hormones and microbiota‐modulated peptides contribute to bone metabolism. Ghrelin, a peptide hormone primarily produced in the gastrointestinal tract, was initially identified as a growth hormone secretagogue and is now increasingly recognized as an important regulator of skeletal metabolism and cellular energetics. Beyond its endocrine functions, ghrelin has been implicated in promoting osteoblast proliferation, differentiation, and survival through AMP‐activated protein kinase (AMPK)‐dependent metabolic pathways, thereby linking energy sensing to bone formation and remodeling (Delhanty et al. 2012). Furthermore, both acylated and unacylated forms of ghrelin have demonstrated protective effects against oxidative stress, mitochondrial dysfunction, and endothelial apoptosis under hyperglycemic and hyperlipidemic conditions through modulation of c‐Jun N‐terminal kinase (JNK) and p38 signaling pathways (Liao et al. 2018; C.‐R. Wu et al. 2021). Studies also suggest that acylated and unacylated ghrelin may exert context‐dependent anti‐inflammatory and metabolic regulatory effects in cancer‐associated cachexia and metabolic dysfunction, highlighting their potential therapeutic relevance in cancer patients (Khatib et al. 2018; Zeng et al. 2020).

Glucagon‐like peptides (GLP‐1 and GLP‐2), secreted by intestinal L‐cells, further contribute to skeletal metabolism by enhancing calcium absorption and directly stimulating osteoblast activity (Montes Castillo et al. 2019). Recent studies suggest that GLP‐1 receptor signaling also influences bone metabolism indirectly through modulation of insulin sensitivity and systemic energy homeostasis, thereby integrating endocrine and metabolic regulation of bone (Yamada et al. 2008; Zheng et al. 2024). Additionally, fibroblast growth factor 23 (FGF23), produced by osteocytes in response to phosphate levels, regulates vitamin D metabolism and phosphate homeostasis, forming a critical feedback loop between bone and mineral metabolism (Guo and Yuan 2015). The gut microbiota represents a central component of the gut‐bone axis, significantly influencing bone density and strength. SCFAs, including butyrate, propionate, and acetate, are produced through microbial fermentation of dietary fibers and play essential roles in calcium absorption and osteoclast regulation (Feng et al. 2024). SCFAs, including butyrate, propionate, and acetate, synthesized by gut microbiota, stimulate signaling pathways that enhance the expression of osteoprotective proteins, notably osteoprotegerin (OPG). OPG functions as a mimic receptor for receptor activators of nuclear factor kappa‐B ligand (RANKL), a protein that facilitates osteoclast development. OPG mitigates bone resorption and preserves bone density by suppressing RANKL (Amin et al. 2020; Y. Wu et al. 2023). Mechanistically, SCFAs function as histone deacetylase (HDAC) inhibitors, thereby modulating epigenetic landscapes that regulate osteoblast differentiation and immune‐mediated bone remodeling (Lucas et al. 2018). Dysbiosis disrupts this balance, leading to increased production of pro‐inflammatory cytokines, including TNF‐α, IL‐6, and IL‐1β, which promote osteoclastogenesis via the RANK/RANKL pathway (P. Zhou et al. 2022). Conversely, anti‐inflammatory cytokines such as IL‐10 mitigate inflammation and protect against bone loss (Q. Zhang et al. 2014). Importantly, studies highlight that mechanical forces and microbiota‐derived metabolites converge on shared signaling pathways, including YAP/TAZ and Wnt signaling, to coordinately regulate bone remodeling and metabolic activity (Chen et al. 2025; Han et al. 2025; Javanmard and Ertürk 2025). This mechanometabolic integration underscores the gut‐bone axis as a dynamic system in which physical cues, microbial metabolites, and endocrine signals collectively govern skeletal homeostasis and disease progression (Figure 2).

Figure 2.

Mechanometabolic regulation of the gut‐bone axis. Gut‐derived hormones, microbiota‐derived metabolites, and mineral/vitamin absorption pathways interact with immune mediators and biomechanical loading to regulate bone homeostasis. These signals converge on key mechanotransduction pathways, including YAP/TAZ, Wnt/β‐catenin, FGFR, and integrin signaling, thereby coordinating osteogenesis, matrix mineralization, osteoimmune responses, and bone remodeling balance.

The gut‐bone axis functions as a bidirectional mechanometabolic network rather than a purely unidirectional gut‐to‐bone signaling pathway. In addition to microbiota‐derived metabolites regulating skeletal homeostasis, mechanical loading of the skeleton itself may influence gastrointestinal physiology, microbial composition, and intestinal barrier integrity through endocrine, immune, and neurohumoral signaling mechanisms. Mechanical stimulation generated during physical activity and skeletal loading has been shown to alter systemic cytokine profiles, myokine secretion, and osteokine signaling, thereby indirectly modulating gut microbial ecology and intestinal metabolism (Karl et al. 2017). Exercise‐induced mechanical loading can increase microbial diversity and promote the expansion of SCFA‐producing bacterial populations, leading to enhanced intestinal barrier integrity and reduced systemic inflammation (Lucas et al. 2018). Mechanistically, mechanical loading stimulates osteocytes and osteoblasts to release bone‐derived endocrine mediators, including osteocalcin and fibroblast growth factor‐23 (FGF23), which may influence intestinal nutrient absorption, phosphate homeostasis, and gut metabolic signaling pathways.

Recent studies further indicate that skeletal mechanotransduction can regulate intestinal immune homeostasis through osteoimmune interactions. Mechanical loading suppresses osteoclastogenic inflammatory cytokines such as TNF‐α and IL‐6 while promoting anti‐inflammatory mediators that preserve intestinal epithelial integrity and reduce gut permeability (Yan et al. 2016). Conversely, mechanical unloading and sedentary behavior are associated with dysbiosis, impaired intestinal tight‐junction integrity, reduced SCFA production, and systemic low‐grade inflammation, all of which contribute to bone loss and metabolic dysfunction. In murine models, exercise‐induced skeletal loading has been linked to increased expression of tight‐junction proteins including occludin and zonula occludens‐1 (ZO‐1), suggesting that biomechanical activity can directly improve gut barrier function through systemic mechanometabolic signaling (Allen et al. 2018). In addition, mechanobiological regulation of the gut‐bone axis may involve neuroendocrine pathways integrating skeletal loading with gastrointestinal function. Mechanical forces generated during exercise activate sympathetic and parasympathetic signaling networks that modulate intestinal motility, mucosal immunity, and microbial composition. These findings collectively support the concept that biomechanical loading of the skeleton can feedback to the gastrointestinal system, thereby establishing a dynamic bidirectional gut‐bone mechanometabolic axis (Zaiss et al. 2019). Nevertheless, the precise molecular intermediates linking skeletal mechanotransduction to microbiota remodeling remain incompletely understood, and further investigation is required to determine how tissue‐specific mechanical environments influence systemic microbial and metabolic homeostasis.

5. Mechanotransduction and Epigenetic Regulation in T2DM

T2DM is a chronic metabolic disorder characterized by hyperglycemia resulting from impaired insulin secretion and peripheral insulin resistance. Glucose enters pancreatic β‐cells via glucose transporter 2 (GLUT2) and is metabolized to generate adenosine triphosphate (ATP), increasing the ATP/adenosine diphosphate (ADP) ratio, which triggers closure of ATP‐sensitive potassium channels, membrane depolarization, and activation of voltage‐gated calcium channels. The resulting calcium influx promotes insulin secretion from secretory granules, thereby maintaining glucose homeostasis under physiological conditions (Buteau et al. 2001). Beyond classical glucose sensing, recent evidence indicates that β‐cell function is highly sensitive to biomechanical cues, including ECM stiffness and cytoskeletal tension, which regulate insulin secretion and β‐cell survival through mechanotransduction pathways.

In individuals with T2DM, epigenetic dysregulation plays a central role in β‐cell dysfunction. The insulin promoter undergoes DNA methylation in pancreatic islet cells, impairing insulin gene expression (Yang et al. 2011). Additionally, genes such as GLRA1, RASD1, SLCO5A1, and CHRNA5 exhibit altered methylation patterns under hyperglycemic conditions. The pancreatic duodenal homeobox‐1 (PDX‐1) transcription factor, a key regulator of β‐cell development and function, is significantly hypermethylated in T2DM, contributing to impaired insulin secretion (Ashizawa et al. 2004; Hall et al. 2018; J. Liu et al. 2021). Patients with T2DM also exhibit reduced mitochondrial electron transport chain (ETC) activity, reflecting impaired bioenergetics (Hall et al. 2018).

Mitochondria, as primary sources of ROS, play a critical role in insulin signaling and glucose metabolism. Elevated ROS levels impair GLUT4 translocation and disrupt insulin signaling pathways, contributing to insulin resistance. Hyperglycemia‐induced metabolic stress, including hypermethylation of mitochondrial NADH‐dehydrogenase‐6 (ND6), further exacerbates mitochondrial dysfunction in obese and diabetic individuals (Ritov et al. 2005). This progressive mitochondrial impairment leads to a decline in β‐cell mass and function, worsening glycemic control. The Wnt/β‐catenin pathway has been identified as a key regulator of β‐cell failure and metabolic dysregulation (Cao et al. 2021; Sha et al. 2020). Importantly, emerging studies demonstrate that YAP/TAZ signaling acts as a mechanosensitive regulator of β‐cell proliferation, survival, and metabolic adaptation. Increased ECM stiffness and cytoskeletal remodeling promote YAP/TAZ nuclear localization, which enhances glycolytic activity and β‐cell proliferation, whereas dysregulated activation may contribute to β‐cell dedifferentiation and dysfunction (Cebola et al. 2015; Yuan et al. 2016). Furthermore, mechanotransduction‐mediated activation of YAP/TAZ has been linked to insulin resistance in peripheral tissues by modulating inflammatory signaling and lipid metabolism, thereby integrating mechanical stress with systemic metabolic dysregulation (Koo and Guan 2018; Lee et al. 2026).

Glycogen synthase kinase‐3β (GSK‐3β) has emerged as a critical regulator of insulin signaling by phosphorylating and inactivating insulin receptor substrate‐1 (IRS‐1), thereby impairing downstream signaling pathways. As a component of the β‐catenin destruction complex, GSK‐3β also links insulin resistance with Wnt signaling dysregulation. Its involvement in glycogen synthesis, gluconeogenesis, and lipid metabolism underscores its therapeutic potential, with GSK‐3 inhibitors showing improved insulin sensitivity in preclinical models (Lemon et al. 2024; Leng et al. 2010). However, given its role in essential cellular processes such as proliferation and survival, therapeutic targeting requires careful modulation. Epigenetic regulation plays a central role in T2DM pathogenesis, with DNA methylation, histone modifications, and chromatin remodeling contributing to altered gene expression (Klimczak and Śliwińska 2024; Ling and Rönn 2019). Histone acetylation, mediated by lysine acetyltransferases, regulates chromatin accessibility and gene transcription. Upregulation of histone deacetylase 7 (HDAC7) in pancreatic cells has been associated with reduced glucose‐stimulated insulin secretion, whereas histone deacetylase inhibitors improve insulin sensitivity by enhancing acetylation of insulin receptor substrate 2 (IRS2) (Kawada et al. 2017; Y. Wang et al. 2023). GLP‐1 receptor agonists, widely used in T2DM therapy, exert protective effects on β‐cells by promoting epigenetic remodeling and reactivation of PDX‐1 transcription, thereby enhancing chromatin accessibility and gene expression (Shvedunova and Akhtar 2022). Notably, research suggest that GLP‐1 signaling also interacts with mechanotransduction pathways, influencing cytoskeletal organization and cellular metabolism, thereby providing a mechanistic link between incretin biology and biomechanical regulation (Holst et al. 2019; Rowlands et al. 2018).

Recent studies claim that mechanical stress within the pancreatic microenvironment directly influences epigenetic remodeling, thereby linking mechanotransduction with β‐cell dysfunction and metabolic dysregulation in T2DM. Pancreatic islets are highly mechanosensitive structures in which ECM stiffness, cytoskeletal tension, and altered tissue viscoelasticity regulate β‐cell survival, insulin secretion, and chromatin organization through force‐dependent signaling pathways (Johansen et al. 2024). Under diabetic conditions, progressive fibrosis and ECM remodeling increase pancreatic tissue stiffness, activating integrin‐FAK‐Src and RhoA/ROCK‐mediated mechanotransduction pathways that converge on nuclear mechanosensors including YAP/TAZ signaling and mechanoresponsive chromatin regulators (Dandapani and Hwang 2026; Johansen et al. 2024). Mechanical stress has been shown to regulate epigenetic modifiers through cytoskeletal‐nuclear coupling mechanisms involving the LINC complex, nuclear lamina remodeling, and chromatin reorganization. Increased actomyosin tension promotes nuclear deformation and alters chromatin accessibility, thereby facilitating recruitment of HDACs, DNA methyltransferases (DNMTs), and chromatin‐remodeling complexes to metabolically relevant gene loci (Nam et al. 2026; Nava et al. 2020). In pancreatic β‐cells, matrix stiffening and oxidative stress are associated with increased HDAC activity and hypermethylation of insulin‐regulatory genes including pancreatic duodenal homeobox‐1 (PDX‐1), leading to impaired insulin transcription and β‐cell dedifferentiation. HDAC7 upregulation, previously associated with reduced glucose‐stimulated insulin secretion, may therefore represent a mechanosensitive epigenetic response to altered pancreatic biomechanics (Ling and Rönn 2019).

Recent studies further indicate that YAP/TAZ signaling itself can directly interact with epigenetic regulatory machinery. Nuclear YAP/TAZ has been shown to recruit histone acetyltransferases and chromatin‐remodeling proteins that modulate transcription of glycolytic and proliferative genes under mechanically activated conditions (Lopez‐Hernandez et al. 2021). Conversely, chronic mechanical stress and inflammatory signaling may promote DNMT‐mediated silencing of β‐cell functional genes, thereby reinforcing metabolic dysfunction and insulin resistance. Mechanical activation of RhoA/ROCK signaling has also been implicated in histone modification and chromatin condensation through regulation of actin polymerization and nuclear mechanotransduction pathways (Chaudhry and Sif 2026; Maurer and Lammerding 2019).

In addition, emerging mechanometabolic models propose that persistent ECM stiffening establishes a self‐amplifying pathological feedback loop in diabetic tissues, where fibrosis‐induced mechanical stress promotes epigenetic repression of insulin‐regulatory genes, mitochondrial dysfunction, inflammatory signaling, and impaired metabolic adaptation (Nam et al. 2026). However, the precise mechanisms by which specific mechanical forces selectively recruit HDACs, DNMTs, and chromatin‐modifying complexes in β‐cells remain incompletely understood and require further investigation using physiologically relevant three‐dimensional and organ‐on‐chip pancreatic models. Overall, the studies highlight that T2DM is not solely a metabolic or endocrine disorder but a mechanometabolic disease in which biomechanical forces, epigenetic modifications, and mitochondrial dysfunction converge to drive β‐cell failure and systemic insulin resistance. Targeting these interconnected mechanometabolic pathways offers a promising avenue for next‐generation therapeutic strategies.

6. Viscoelasticity as a Driver of Mechanotransduction and Metabolic Reprogramming

Viscoelasticity is a fundamental mechanical property of biological systems, encompassing cells, multicellular spheroids, and tissues, which exhibit both viscous and elastic behavior under deformation (Mierke 2022). This property plays a crucial role in regulating cellular development, motility, and tissue homeostasis, and is increasingly implicated in pathological conditions such as cancer, fibrosis, and inflammation (Courbot and Elosegui‐Artola 2025). The viscoelastic characteristics of the ECM and cancer cells significantly influence tumor progression by modulating cellular force transmission and microenvironmental stiffness (Mierke 2021). Importantly, viscoelasticity is not merely a passive mechanical property but actively regulates cellular signaling through mechanotransduction pathways, including YAP/TAZ signaling, thereby linking physical properties of tissues to metabolic and transcriptional reprogramming (Sirio Dupont et al. 2011; Panciera et al. 2017).

Significant differences in viscoelastic properties are observed between two‐dimensional (2D) and three‐dimensional (3D) culture systems, with 3D environments more accurately recapitulating in vivo mechanical conditions. These differences have critical implications for drug development, as 2D‐based screening platforms often fail to predict therapeutic responses due to the absence of physiologically relevant mechanical cues. The viscoelastic response of cells, governed by intracellular friction and cytoskeletal organization, determines their ability to adapt to external forces (Smithmyer et al. 2019). Reduced viscoelastic resistance enhances cellular deformability, thereby increasing migratory and invasive potential, particularly in cancer cells (Kalwarczyk et al. 2011; Z. Liu et al. 2020). This mechanical plasticity is closely associated with metabolic reprogramming, where highly deformable cells exhibit increased glycolytic flux and biosynthetic activity to support rapid proliferation and invasion. Viscoelasticity also serves as a defining mechanical signature of immune cells, influencing their activation, migration, and functional responses (Zak et al. 2021). The sustained viscoelastic properties of immune cells enable their participation in dynamic processes such as wound healing and inflammation. In lung epithelial wound repair, local mechanical gradients regulate collective cell migration and proliferation, underscoring the role of viscoelasticity in tissue regeneration (Wagh et al. 2008). Evidence suggests that immune cell viscoelasticity is tightly coupled to immunometabolism, where cytoskeletal remodeling influences metabolic pathways such as glycolysis and oxidative phosphorylation, thereby shaping immune responses (Guak and Krawczyk 2020; T. Hu et al. 2024).

Viscoelasticity is a universal property observed across organ systems, including the liver and lungs, which are particularly susceptible to fibrosis and inflammatory remodeling (Gao et al. 2010). Fibrosis is characterized by excessive ECM deposition, leading to increased tissue stiffness and altered viscoelastic behavior. These changes can be modeled using rheological frameworks such as the Maxwell model, which describes time‐dependent stress relaxation and deformation (Ayyildiz et al. 2015; Chui et al. 2004). Importantly, progressive stiffening of tissues during fibrosis activates mechanosensitive pathways, including YAP/TAZ and TGF‐β signaling, thereby promoting fibroblast activation and metabolic shifts toward anabolic and profibrotic states. Mechanical forces directly influence cellular metabolism through biotransduction mechanisms. In epithelial cells, mechanical stress alters glycolytic enzyme activity, linking cytoskeletal dynamics to glucose metabolism. Shear stress induces AMPK‐dependent lipophagy in renal epithelial cells, increasing fatty acid availability for ATP production via β‐oxidation (Miceli et al. 2020). Furthermore, mechanical cues regulate mitochondrial dynamics, including biogenesis, fission, and function. Activation of AMPK under shear stress promotes phosphorylation of PGC‐1α, enhancing mitochondrial biogenesis, while cells cultured on compliant substrates exhibit increased mitochondrial fission and elevated mitochondrial reactive oxygen species (mtROS) production (Romani et al. 2022).

Notably, mitochondria themselves exhibit viscoelastic properties, and their mechanical adaptability influences metabolic efficiency and redox balance. Increased mtROS levels activate NRF2‐mediated antioxidant responses, enhancing cellular resilience to oxidative stress. Additionally, ECM stiffness‐dependent activation of DRP1 regulates mitochondrial fission and ROS homeostasis, linking mechanical cues to metabolic adaptation (Papalazarou et al. 2020; Romani et al. 2022). Despite these advances, the mechanistic understanding of how mitochondrial mechanics integrate with cellular viscoelasticity and metabolic feedback remains incomplete. Recent studies utilizing deformability cytometry and real‐time fluorescence imaging have begun to elucidate the mechanical behavior of mitochondria and their response to metabolic cues (Su et al. 2023).

Beyond its role in regulating cellular energetics and mechanotransduction, viscoelasticity has emerged as a promising therapeutic target in mechanomedicine. Pathological alterations in tissue viscoelasticity are increasingly recognized as modifiable drivers of fibrosis, tumor progression, metabolic dysfunction, and impaired tissue regeneration (Mierke 2022). Therapeutic strategies aimed at restoring physiological mechanical properties of tissues can directly influence mechanotransduction pathways, cellular metabolism, and disease progression. In fibrotic tissues, ECM deposition increases tissue stiffness and viscoelastic resistance, leading to persistent activation of mechanosensitive signaling pathways including YAP/TAZ signaling, TGF‐β, and integrin‐FAK signaling (Lei et al. 2025). Pharmacological inhibition of these pathways has demonstrated potential to reverse pathological mechanometabolic activation and reduce fibrosis‐associated metabolic remodeling (F. Liu et al. 2015). Recent studies have shown that targeting cytoskeletal tension and matrix mechanics can modulate mitochondrial function, glycolytic activity, and ROS production (Bartolák‐Suki et al. 2017). In cancer, reduction of ECM stiffness using matrix‐modifying agents or FAK inhibitors suppresses YAP/TAZ nuclear localization, thereby reducing glycolytic reprogramming, proliferation, and invasive potential (Liang and Song 2023; Panciera et al. 2017). Similarly, inhibition of actomyosin contractility through ROCK inhibitors has been shown to restore normal cellular viscoelasticity and attenuate fibrosis‐associated metabolic dysfunction (Henderson et al. 2020; You et al. 2020). These findings suggest that modulation of tissue viscoelasticity may represent an effective strategy for correcting aberrant mechanometabolic signaling in multiple disease contexts.

Mechanotherapeutic biomaterials have also emerged as important tools for regulating viscoelastic‐dependent cellular metabolism. Hydrogels with tunable stiffness and stress‐relaxation properties can modulate stem‐cell differentiation, mitochondrial biogenesis, and anabolic metabolism by controlling cellular force sensing and nuclear mechanotransduction (Chaudhuri et al. 2016). Dynamic biomaterials capable of mimicking physiological viscoelasticity have shown improved outcomes in cartilage regeneration, wound healing, and muscle repair by restoring appropriate biomechanical and metabolic microenvironments. In addition, viscoelastic biomaterials can regulate immune‐cell activation and inflammatory metabolism, thereby improving tissue integration and regenerative responses. New therapeutic approaches further include the use of mechanosensitive ion‐channel modulators, matrix‐degrading enzymes, and adaptive biomaterials that dynamically respond to mechanical loading (X. Lin et al. 2024). Piezo1‐targeted therapies, for example, have demonstrated potential in regulating calcium‐dependent mechanotransduction and metabolic adaptation in vascular and musculoskeletal disorders (J. Li et al. 2014). Furthermore, recent advances in organ‐on‐chip systems and mechanoresponsive drug‐delivery platforms provide new opportunities for investigating viscoelastic regulation in physiologically relevant environments and for developing personalized mechanotherapeutic strategies (Akhtar and Gupta 2024). Despite these advances, therapeutic targeting of viscoelasticity remains challenging due to tissue‐specific mechanical heterogeneity and the context‐dependent nature of mechanotransduction signaling. Excessive suppression of mechanical signaling may impair normal tissue regeneration and homeostasis, highlighting the need for precise modulation of biomechanical pathways. Future studies integrating viscoelastic profiling, mechanotranscriptomics, and spatial metabolomics are expected to improve the development of targeted mechanometabolic therapies for chronic inflammatory, fibrotic, metabolic, and degenerative diseases (Table 3).

Table 3.

Mechanobiology‐driven therapeutic strategies targeting metabolic reprogramming and tissue mechanics.

Therapeutic strategy	Primary mechanobiological target	Representative molecules/tools	Disease context	Mechanistic basis	Level of evidence	Clinical status	References
YAP/TAZ inhibition	YAP/TAZ signaling and TEAD‐dependent transcription	Verteporfin, TEAD inhibitors (VT3989)	Fibrosis, solid tumors	Suppresses mechanosensitive transcription, glycolytic reprogramming, and fibroblast activation	Predominantly in vitro and animal studies	Early clinical/preclinical development	F. Liu et al. (2015); Panciera et al. (2017)
Integrin targeting	ECM sensing and focal adhesion signaling	Cilengitide, integrin antagonists	Fibrosis, glioblastoma, tumor progression	Disrupts integrin‐FAK‐mediated cell‐ECM mechanosignaling	Animal studies and clinical trials	Clinical trials	Desgrosellier and Cheresh (2010)
AMPK activation	Cellular energy sensing and metabolic adaptation	Metformin, AICAR	Type 2 diabetes mellitus, cardiovascular disease	Restores mitochondrial energetics and suppresses inflammatory metabolism	Extensive animal and human clinical evidence	Approved therapy	Foretz et al. (2014)
Biomaterial scaffolds	ECM mimicry and cellular mechanoregulation	Hydrogels, electrospun nanofibers	Tissue regeneration, wound healing	Modulates substrate stiffness, cell fate, and metabolic adaptation	In vitro and translational preclinical studies	Translational development	Chaudhuri et al. (2016)
Mechanotherapy	Load‐dependent mechanotransduction	Mechanical loading devices, rehabilitation systems	Osteoporosis, muscle wasting	Activates osteogenic and regenerative mechanosensitive pathways	Human clinical and rehabilitation studies	Clinical use	Robling and Turner (2009)
GLP‐1 receptor agonists	Metabolic regulation with indirect mechanometabolic effects	Liraglutide, Semaglutide	Type 2 diabetes mellitus, obesity‐associated cardiovascular disease	Improves β‐cell metabolism, mitochondrial function, and endothelial homeostasis	Extensive human clinical evidence	Approved therapy	Drucker (2018)
Anti‐fibrotic therapy	ECM remodeling and tissue stiffening	Pirfenidone, TGF‐β inhibitors	Pulmonary and liver fibrosis	Reduces ECM deposition, tissue stiffness, and pro‐fibrotic signaling	Animal and human clinical studies	Approved/clinical trials	Henderson et al. (2020)
Ion‐channel modulation	Mechanosensitive ion signaling	Piezo1 modulators, GsMTx4	Vascular dysfunction, fibrosis	Regulates Ca2+‐dependent mechanotransduction and cytoskeletal remodeling	Primarily experimental and animal studies	Emerging/preclinical	J. Li et al. (2014)
Immunometabolic targeting	Epigenetic and inflammatory metabolic regulation	HDAC inhibitors	Cancer, chronic inflammation	Alters chromatin accessibility, inflammatory signaling, and metabolic adaptation	Clinical and preclinical evidence	Clinical trials	San‐Miguel et al. (2014)
Smart biomaterials	Adaptive viscoelastic mechanoregulation	Stimuli‐responsive scaffolds	Regenerative medicine	Dynamically modulates force transmission and cellular metabolism	In vitro and translational studies	Emerging technology	Huebsch et al. (2015)

7. Mechanobiomaterials in Tissue Repair and Metabolic Regeneration

Biomaterials have emerged as critical modulators of tissue repair, functioning not only as structural scaffolds but also as active regulators of cellular mechanotransduction and metabolic reprogramming. Contemporary biomaterial design increasingly integrates mechanical, biochemical, and biophysical cues to recapitulate the native ECM microenvironment, thereby directing cell fate and functional regeneration (X. Lin et al. 2020). Mechanical stimuli including matrix stiffness, viscoelasticity, tensile strain, and shear stress are now recognized as essential determinants of cellular behavior, influencing proliferation, differentiation, and survival through force‐sensitive signaling networks. These cues are transduced via integrins, focal adhesion complexes, mechanosensitive ion channels, and cytoskeletal remodeling, ultimately converging on transcriptional regulators such as YAP/TAZ signaling, which couple extracellular mechanics to gene expression and metabolic control (Sirio Dupont et al. 2011; Katoh 2025; Long et al. 2025).

Mechanobiomaterials restore disrupted tissue mechanics following injury, thereby re‐establishing homeostatic signaling required for regeneration. Implantation of engineered scaffolds normalizes aberrant stress distributions, promoting cell recruitment, proliferation, and lineage‐specific differentiation while simultaneously regulating local metabolic activity. Importantly, these materials do not merely provide passive support but actively modulate intracellular metabolic pathways, including glycolysis, oxidative phosphorylation, and lipid metabolism, which are essential for tissue repair (X. Lin et al. 2024; Oluwole et al. 2026). Mechanical cues delivered by biomaterials have been shown to activate AMPK signaling, enhancing mitochondrial biogenesis and energy efficiency in metabolically active tissues such as muscle and bone (Garcia and Shaw 2017; Scott 2010). In parallel, substrate stiffness and matrix architecture influence mitochondrial dynamics, including fission and fusion processes, thereby regulating cellular redox balance and biosynthetic capacity.

Recent advances in biomaterial engineering have enabled the development of tissue‐specific scaffolds with tunable mechanical and biochemical properties. In bone regeneration, calcium phosphate‐based biomaterials and collagen composites promote osteoblast differentiation and mineral deposition through mechanosensitive pathways, including YAP/TAZ and Wnt/β‐catenin signaling (Jeong et al. 2019; Vyas et al. 2025). Growth factors such as bone morphogenetic proteins (BMPs) further enhance osteogenesis by integrating biochemical signaling with mechanical cues. In cartilage repair, hydrogels with dynamic stiffness and viscoelastic properties mimic the load‐bearing environment of native cartilage, facilitating chondrocyte activity and ECM synthesis (Vega et al. 2017). Similarly, electrospun scaffolds provide structural anisotropy that supports cellular alignment and tissue organization.

In skeletal muscle regeneration, biomaterials designed to promote cellular alignment and angiogenesis are critical for restoring contractile function. Fiber‐based scaffolds enhance myocyte differentiation, while incorporation of angiogenic factors improves vascularization, ensuring adequate oxygen and nutrient supply to regenerating tissue (Flores‐Rojas et al. 2023; Rockwood et al. 2008). In cutaneous wound healing, advanced biomaterials such as multifunctional hydrogels provide mechanical protection while delivering antimicrobial and bioactive agents that stimulate fibroblast proliferation, collagen deposition, and tissue remodeling. These systems are particularly effective in chronic wounds, including diabetic ulcers, where impaired mechanotransduction and metabolic dysfunction hinder healing (Mao et al. 2022). Overall, biomaterials represent a powerful platform for integrating mechanical and metabolic signals to drive tissue regeneration. By modulating mechanotransduction pathways and cellular energetics, mechanobiomaterials enable precise control over tissue repair processes (Figure 3). Future developments focusing on adaptive, stimuli‐responsive biomaterials and their integration with mechanometabolic signaling networks hold significant promise for advancing regenerative medicine and developing next‐generation therapeutic strategies.

Figure 3.

Mechanobiomaterial‐mediated activation of mechanotransduction pathways drives metabolic reprogramming and regenerative cellular responses. Mechanical cues transmitted through integrins, focal adhesions, and mechanosensitive ion channels activate the FAK/Src‐RhoA/ROCK‐YAP/TAZ signaling axis, leading to metabolic adaptations including enhanced mitochondrial biogenesis, glycolysis, antioxidant defense, anabolic biosynthesis, and autophagy. These mechanometabolic responses collectively promote proliferation, osteogenic differentiation, extracellular matrix synthesis, angiogenesis, and tissue resilience, thereby supporting tissue repair and regeneration.

8. Context‐Dependent Roles and Translational Limitations of Mechanotransduction Signaling

Although mechanotransduction pathways are increasingly recognized as central regulators of metabolic adaptation and disease progression, the biological effects of these signaling networks remain highly context dependent. In particular, YAP/TAZ signaling exhibits both adaptive and maladaptive functions depending on cell type, tissue microenvironment, duration of activation, and pathological context. Acute YAP/TAZ activation may support tissue repair, stem‐cell maintenance, mitochondrial adaptation, and regenerative responses following transient mechanical injury. In contrast, persistent activation under chronic ECM stiffening or inflammatory conditions has been associated with fibrosis, tumor progression, endothelial dysfunction, and metabolic dysregulation (Sirio Dupont et al. 2011; Panciera et al. 2017). For example, transient YAP activation promotes cardiomyocyte proliferation and regenerative repair following cardiac injury, whereas prolonged activation contributes to pathological cardiac remodeling and fibrosis through sustained fibroblast activation and ECM deposition (Byun et al. 2019). Similarly, YAP/TAZ signaling can enhance metabolic flexibility and survival in stem cells and regenerating tissues while simultaneously promoting glycolytic reprogramming and proliferative metabolism in cancer cells (Vining and Mooney 2017).

Importantly, much of the current mechanobiology literature is derived from 2D in vitro culture systems that incompletely replicate the complex viscoelasticity, ECM heterogeneity, and biomechanical loading patterns present in vivo. Cellular responses to substrate stiffness in simplified culture conditions may differ substantially from those observed in animal models or human tissues, where mechanical signaling is dynamically integrated with inflammatory, endocrine, immune, and metabolic networks (Bhardwaj et al. 2024; Maurer and Lammerding 2019). Furthermore, several mechanotransduction pathways display tissue‐specific responses to identical mechanical stimuli. For instance, increased ECM stiffness promotes osteogenic differentiation in skeletal tissues but may induce fibrosis and pathological metabolic remodeling in cardiac, hepatic, or pulmonary tissues (Panciera et al. 2017; Tiskratok et al. 2025). These observations highlight the need for careful interpretation of mechanobiological findings across different experimental systems and disease models.

Conflicting findings have also been reported regarding the therapeutic targeting of mechanotransduction pathways. While inhibition of YAP/TAZ signaling has demonstrated beneficial effects in fibrosis and cancer models, excessive suppression of mechanosensitive pathways may impair normal tissue regeneration, wound healing, and stem‐cell function (Sirio Dupont et al. 2011; S. Piccolo et al. 2023). Similarly, modulation of ECM stiffness or cytoskeletal tension may produce beneficial metabolic effects in some tissues while disrupting homeostatic biomechanics in others (Ge et al. 2021). These limitations emphasize that mechanotransduction pathways should not be considered universally pathological or universally protective, but rather as dynamic regulators whose effects depend on temporal, spatial, and tissue‐specific biological contexts. In addition, translational challenges remain significant due to differences between animal models and human disease progression. Many preclinical mechanobiology studies rely on short‐term experimental models that may not accurately recapitulate chronic human diseases such as fibrosis, diabetes mellitus, or atherosclerosis. Emerging technologies including three‐dimensional organoid systems, organ‐on‐chip platforms, spatial metabolomics, and mechanotranscriptomic profiling are expected to improve physiological relevance and enable more accurate investigation of mechanometabolic regulation in human tissues (Vining and Mooney 2017). Future studies integrating biomechanics, metabolism, epigenetics, and immune signaling will be essential for developing targeted mechanotherapeutic strategies with improved tissue specificity and clinical applicability.

9. Future Perspectives

The integration of mechanobiology with medicine is expected to accelerate substantially as emerging technologies continue to refine the understanding of how biomechanical forces regulate cellular metabolism, tissue remodeling, and disease progression across complex physiological systems. Recent advances in non‐invasive in vivo imaging modalities, including magnetic resonance elastography and ultrasound elastography, together with high‐resolution ex vivo approaches such as atomic force microscopy, have significantly improved the ability to quantify tissue stiffness, viscoelasticity, and biomechanical heterogeneity during disease progression (Stylianou et al. 2018; Tan and Venkatesh 2016). These technologies are increasingly being complemented by single‐cell mechanotranscriptomics, spatial transcriptomics, and spatial metabolomics, enabling the simultaneous mapping of mechanical cues, metabolic states, and transcriptional responses within intact tissue microenvironments with unprecedented spatial resolution (Alexandrov 2020). Such integrative approaches are expected to substantially improve understanding of tissue‐specific mechanometabolic heterogeneity in fibrosis, cardiovascular diseases, diabetes, cancer, and regenerative disorders.

Future progress in the field will likely depend on the development of physiologically relevant experimental platforms capable of replicating dynamic biomechanical and metabolic interactions observed in vivo. Current mechanobiology research remains heavily dependent on simplified two‐dimensional culture systems that inadequately model tissue viscoelasticity, multicellular organization, immune interactions, and metabolic complexity. In this context, organ‐on‐chip and microphysiological systems have emerged as promising translational platforms for reproducing tissue‐specific mechanical loading, ECM remodeling, vascular flow, and cellular metabolic adaptation under controlled conditions (Huh et al. 2010; Ingber 2022). These systems may enable more accurate investigation of mechanotransduction‐mediated metabolic regulation while improving therapeutic screening, disease modeling, and personalized medicine applications. Importantly, the emergence of precision mechanomedicine aims to integrate patient‐specific biomechanical signatures with molecular, metabolic, and epigenetic profiling to guide targeted therapeutic interventions. However, major challenges remain due to the highly context‐dependent nature of mechanotransduction, where identical mechanical stimuli may induce adaptive or pathological responses depending on tissue type, inflammatory status, ECM composition, and disease stage. In particular, the dual physiological and pathological roles of YAP/TAZ signaling continue to complicate the development of safe mechanotherapeutic strategies. Pharmacological modulation of YAP/TAZ signaling, integrin‐FAK pathways, mechanosensitive ion channels, and cytoskeletal tension networks is increasingly being explored to correct aberrant mechanometabolic signaling in fibrosis, cardiovascular remodeling, cancer progression, and metabolic disease, although maintaining physiological tissue homeostasis during such interventions remains a significant challenge (Panciera et al. 2017).

The integration of AI, computational mechanobiology, and machine‐learning approaches is also expected to transform the field by enabling predictive modeling of force‐dependent signaling networks, ECM remodeling, and metabolic adaptation across heterogeneous tissues (Topol 2019). AI‐assisted multi‐omics analysis may facilitate identification of mechanometabolic biomarkers, prediction of therapeutic responses, and optimization of biomaterial design for regenerative applications. Furthermore, adaptive and stimuli‐responsive biomaterials capable of dynamically modulating tissue stiffness, cellular force transmission, and metabolic signaling are expected to play a critical role in next‐generation regenerative medicine and tissue engineering strategies. Despite substantial progress, several translational barriers remain unresolved, including long‐term biomaterial biocompatibility, precise control of in vivo mechanical environments, tissue‐specific variability in mechanotransduction responses, and the lack of standardized mechanobiological models. Addressing these limitations will require close interdisciplinary collaboration among clinicians, engineers, computational scientists, and biologists. Collectively, the convergence of advanced imaging, organ‐on‐chip systems, spatial omics technologies, AI‐driven mechanobiology, and adaptive biomaterials positions mechanobiology at the forefront of precision medicine and next‐generation therapeutic innovation for cardiovascular, skeletal, endocrine, fibrotic, and degenerative diseases.

10. Conclusion

Mechanobiology‐driven metabolic regulation has emerged as a critical determinant of tissue adaptation and disease progression across cardiovascular, skeletal, and endocrine systems. The growing understanding of how ECM dynamics, cytoskeletal remodeling, and mechanotransduction pathways coordinate cellular metabolism highlights the importance of biomechanical signaling in maintaining physiological homeostasis and promoting pathological remodeling. Nevertheless, significant challenges remain in defining tissue‐specific mechanometabolic responses, distinguishing adaptive from maladaptive YAP/TAZ activation, and translating mechanobiological findings into clinically effective therapies. Current evidence also underscores the need for more physiologically relevant experimental models capable of integrating biomechanics, metabolism, immune signaling, and epigenetic regulation within complex tissue microenvironments. Advancing mechanotherapeutic approaches targeting ECM stiffness, cellular force transmission, and metabolic plasticity may ultimately provide new opportunities for precision medicine and regenerative therapies in chronic metabolic and degenerative diseases.

Author Contributions

Arul Narayanasamy: conceptualization, methodology, formal analysis, investigation, project administration, writing – original draft. Panimalar Abirami Karuppusamy: conceptualization, methodology, formal analysis, investigation, project administration, writing – original draft. Roselin Gnanarajan: formal analysis, investigation, writing – review and editing. Nandita Ravichandran: formal analysis, investigation, writing – review and editing. Deenathayalan Uvarajan: formal analysis, investigation, writing – review and editing. Mahalaxmi Iyer: formal analysis, investigation, writing – review and editing. Jayalakshmi Krishnan: formal analysis, investigation, writing – review and editing. Jyoti Parkash: formal analysis, investigation, writing – review and editing. Dibbanti Harikrishnareddy: formal analysis, investigation, writing – review and editing. Anirban Goutam Mukherjee: formal analysis, investigation, writing – review and editing. Balachandar Vellingiri: formal analysis, investigation, writing – review and editing. Raja Ganesan: conceptualization, methodology, formal analysis, investigation, project administration, writing – original draft.

Funding

The authors have nothing to report.

Disclosure

All figures included in this manuscript are original and created by the authors (https://app.biorender.com).

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Narayanasamy, A. , Karuppusamy P. A., Gnanarajan R., et al. 2026. “Mechanobiology‐Driven Metabolic Reprogramming: Integrative Roles of YAP/TAZ Signaling and Extracellular Matrix Dynamics.” Cell Biology International 50: e70180. 10.1002/cbin.70180.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.