{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:47:09Z","timestamp":1788796029550,"version":"build-2803163510"},"reference-count":61,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cellular behavior is strongly influenced by mechanical signals in the surrounding microenvironment, along with external factors such as temperature fluctuations, changes in blood flow, and muscle activity, etc. These factors are key in shaping cellular states and can contribute to the development of various diseases. In the realm of rehabilitation physical therapies, therapeutic exercise and manual treatments, etc., are frequently employed, not just for pain relief but also to support recovery from diverse health conditions. However, the detailed molecular pathways through which these therapies interact with tissues and influence gene expression are not yet fully understood. The identification of YAP has been instrumental in closing this knowledge gap. YAP is known for its capacity to perceive and translate mechanical signals into specific transcriptional programs within cells. This insight has opened up new perspectives on how physical and rehabilitation medicine may exert its beneficial effects. The review investigates the involvement of the Hippo\/YAP signaling pathway in various diseases and considers how different rehabilitation techniques leverage this pathway to aid in healing. Additionally, it examines the therapeutic potential of modulating the Hippo\/YAP pathway within the context of rehabilitation, while also addressing the challenges and controversies that surround its use in physical and rehabilitation medicine.<\/jats:p>","DOI":"10.3390\/biom15010096","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T08:03:05Z","timestamp":1736496185000},"page":"96","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the Revolutionary Impact of YAP Pathways on Physical and Rehabilitation Medicine"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-6549","authenticated-orcid":false,"given":"Carmelo","family":"Pirri","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Institute of Human Anatomy, University of Padova, 35121 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.devcel.2010.09.011","article-title":"The hippo signaling pathway in development and cancer","volume":"19","author":"Pan","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1038\/ncb2303","article-title":"The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal","volume":"13","author":"Zhao","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.274027.115","article-title":"Mechanisms of Hippo pathway regulation","volume":"30","author":"Meng","year":"2016","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10137","article-title":"Role of YAP\/TAZ in mechanotransduction","volume":"474","author":"Dupont","year":"2011","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.cell.2013.07.042","article-title":"A mechanical checkpoint controls multicellular growth through YAP\/TAZ regulation by actin-processing factors","volume":"154","author":"Aragona","year":"2013","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kim, E., Riehl, B.D., Bouzid, T., Yang, R., Duan, B., Donahue, H.J., and Lim, J.Y. (2024). YAP mechanotransduction under cyclic mechanical stretch loading for mesenchymal stem cell osteogenesis is regulated by ROCK. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1306002"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1152\/japplphysiol.01076.2015","article-title":"The Hippo signal transduction network for exercise physiologists","volume":"120","author":"Gabriel","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1589\/jpts.36.441","article-title":"Effects of local vibration stimulation on muscle recovery and hypertrophy","volume":"36","author":"Ishikura","year":"2024","journal-title":"J. Phys. Ther. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1152\/physrev.00005.2014","article-title":"The biology of YAP\/TAZ: Hippo signaling and beyond","volume":"94","author":"Piccolo","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1101\/gad.210773.112","article-title":"The Hippo pathway: Regulators and regulations","volume":"27","author":"Yu","year":"2013","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1517\/14728222.2012.662958","article-title":"An update on targeting Hippo-YAP signaling in liver cancer","volume":"16","author":"Liu","year":"2012","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nrm.2017.87","article-title":"Mechanobiology of YAP and TAZ in physiology and disease","volume":"18","author":"Panciera","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1101\/gad.1909210","article-title":"The Hippo-YAP pathway in organ size control and tumorigenesis: An updated version","volume":"24","author":"Zhao","year":"2010","journal-title":"Genes Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/s41556-018-0142-z","article-title":"YAP\/TAZ upstream signals and downstream responses","volume":"20","author":"Totaro","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1016\/j.cub.2014.07.034","article-title":"Regulation of YAP by mechanical strain through Jnk and Hippo signaling","volume":"24","author":"Codelia","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/ncb1748","article-title":"TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal","volume":"10","author":"Varelas","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","article-title":"Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer","volume":"163","author":"Yu","year":"2015","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.ccell.2016.05.005","article-title":"YAP\/TAZ at the Roots of Cancer","volume":"29","author":"Zanconato","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41568-023-00579-1","article-title":"Insights into recent findings and clinical application of YAP and TAZ in cancer","volume":"23","author":"Franklin","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.7150\/thno.53438","article-title":"YAP in pancreatic cancer: Oncogenic role and therapeutic strategy","volume":"11","author":"Mao","year":"2021","journal-title":"Theranostics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41586-023-06991-9","article-title":"Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver","volume":"626","author":"Fan","year":"2024","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/hep.32105","article-title":"YAP-TEAD mediates PPAR \u03b1-induced hepatomegaly and liver regeneration in mice","volume":"75","author":"Fan","year":"2022","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1007\/s10620-013-2756-0","article-title":"Regional hepatic regeneration after liver resection correlates well with preceding changes in the regional portal circulation in humans","volume":"58","author":"Iimuro","year":"2013","journal-title":"Dig. Dis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Christ, B., Collatz, M., Dahmen, U., Herrmann, K.H., H\u00f6pfl, S., K\u00f6nig, M., Lambers, L., Marz, M., Meyer, D., and Radde, N. (2021). Hepatectomy-Induced Alterations in Hepatic Perfusion and Function\u2014Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.733868"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"eaba2374","DOI":"10.1126\/science.aba2374","article-title":"Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring","volume":"372","author":"Mascharak","year":"2021","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1002\/jor.23138","article-title":"YAP and ERK mediated mechanical strain-induced cell cycle progression through RhoA and cytoskeletal dynamics in rat growth plate chondrocytes","volume":"34","author":"Yang","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41536-021-00164-w","article-title":"Cyclic pulsation stress promotes bone formation of tissue engineered laminae through the F-actin\/YAP-1\/\u03b2-Catenin signaling axis","volume":"6","author":"Li","year":"2021","journal-title":"NPJ Regen. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.tips.2019.02.004","article-title":"Targeting Mechanosensitive Transcription Factors in Atherosclerosis","volume":"40","author":"Niu","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1161\/ATVBAHA.114.303428","article-title":"Novel mechanisms of endothelial mechanotransduction","volume":"34","author":"Abe","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nature20602","article-title":"Integrin-YAP\/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow","volume":"540","author":"Wang","year":"2016","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI122440","article-title":"c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow","volume":"129","author":"Li","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s10735-013-9502-y","article-title":"YAP-mediated regulation of the chondrogenic phenotype in response to matrix elasticity","volume":"44","author":"Zhong","year":"2013","journal-title":"J. Mol. Histol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"de Lucas, B., P\u00e9rez, L.M., Bernal, A., and G\u00e1lvez, B.G. (2020). Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine. Genes, 11.","DOI":"10.3390\/genes11091086"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Steppe, L., Liedert, A., Ignatius, A., and Haffner-Luntzer, M. (2020). Influence of Low-Magnitude High-Frequency Vibration on Bone Cells and Bone Regeneration. Front. Bioeng. Biotechnol., 8.","DOI":"10.3389\/fbioe.2020.595139"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1249\/MSS.0b013e3182811947","article-title":"Adaptations of mouse skeletal muscle to low-intensity vibration training","volume":"45","author":"McKeehen","year":"2013","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s10735-022-10059-9","article-title":"Role of Yes-associated protein (YAP) in regulation of mesenchymal stem cell tenogenic differentiation","volume":"53","author":"Li","year":"2022","journal-title":"J. Mol. Histol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chen, L., Jin, X., Ma, J., Xiang, B., and Li, X. (2023). YAP at the progression of inflammation. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1204033"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1186\/s12967-024-05086-x","article-title":"Low-intensity pulsed ultrasound delays the progression of osteoarthritis by regulating the YAP-RIPK1-NF-\u03baB axis and influencing autophagy","volume":"22","author":"Pan","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1359\/jbmr.2002.17.2.349","article-title":"Quantity and quality of trabecular bone in the femur are enhanced by a strongly anabolic, noninvasive mechanical intervention","volume":"17","author":"Rubin","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"31","DOI":"10.22203\/eCM.v045a03","article-title":"Uniaxial cyclic stretch enhances osteogenic differentiation of OPLL-derived primary cells via YAP-Wnt\/\u03b2-catenin axis","volume":"45","author":"Zhu","year":"2023","journal-title":"Eur. Cell Mater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1249\/MSS.0000000000003143","article-title":"ELABELA-APJ-Akt\/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats","volume":"55","author":"Xi","year":"2023","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1080\/2000656X.2019.1693393","article-title":"The use of low-intensity pulsed ultrasound in hand and wrist nonunions","volume":"54","author":"Elvey","year":"2020","journal-title":"J. Plast. Surg. Hand Surg."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lin, G., Reed-Maldonado, A.B., Lin, M., Xin, Z., and Lue, T.F. (2016). Effects and Mechanisms of Low-Intensity Pulsed Ultrasound for Chronic Prostatitis and Chronic Pelvic Pain Syndrome. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071057"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/s41420-024-01972-x","article-title":"The roles of Hippo\/YAP signaling pathway in physical therapy","volume":"10","author":"Pan","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1161\/ATVBAHA.112.254730","article-title":"The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation","volume":"32","author":"Wang","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Luo, M., Meng, Z., Moroishi, T., Lin, K.C., Shen, G., Mo, F., Shao, B., Wei, X., Zhang, P., and Wei, Y. (2021). Publisher Correction: Heat stress activates YAP\/TAZ to induce the heat shock transcriptome. Nat. Cell Biol., 23, Erratum for: Nat. Cell Biol. 2020, 22, 1447\u20131459.","DOI":"10.1038\/s41556-020-00602-9"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.yexcr.2013.01.020","article-title":"Yes-associated protein homolog, YAP-1, is involved in the thermotolerance and aging in the nematode Caenorhabditis elegans","volume":"319","author":"Iwasa","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3715471","DOI":"10.1155\/2022\/3715471","article-title":"Periodic Heat Stress Licenses EMSC Differentiation into Osteoblasts via YAP Signaling Pathway Activation","volume":"2022","author":"Shi","year":"2022","journal-title":"Stem Cells Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1083\/jcb.201801143","article-title":"Cold-induced protein RBM3 orchestrates neurogenesis via modulating Yap mRNA stability in cold stress","volume":"217","author":"Xia","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s11427-020-1779-2","article-title":"Cold-induced Yes-associated-protein expression through miR-429 mediates the browning of white adipose tissue","volume":"64","author":"Ye","year":"2021","journal-title":"Sci. China Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.cmet.2018.02.005","article-title":"Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues","volume":"27","author":"Tharp","year":"2018","journal-title":"Cell Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jbiomech.2013.09.024","article-title":"Enhancement of neuromuscular dynamics and strength behavior using extremely low magnitude mechanical signals in mice","volume":"47","author":"Mettlach","year":"2014","journal-title":"J. Biomech."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhu, Z., He, Z., Tang, T., Wang, F., Chen, H., Zhou, J., Lin, C., Chen, G., Wang, J., and Li, J. (2023). Effect of mechanical stimulation on tissue heterotopic ossification: An in vivo experimental study. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1225898"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"852","DOI":"10.2340\/16501977-2385","article-title":"Effects of extracorporeal shock wave therapy on spasticity in post-stroke patients: A systematic review and meta-analysis of randomized controlled trials","volume":"50","author":"Xiang","year":"2018","journal-title":"J. Rehabil. Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Yang, W., He, Y., Gan, L., Zhang, F., Hua, B., Yang, P., Liu, J., Yang, L., and Guo, T. (2018). Cardiac shock wave therapy promotes arteriogenesis of coronary micrangium, and ILK is involved in the biomechanical effects by proteomic analysis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19393-z"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Pirri, C., Caroccia, B., Angelini, A., Piazza, M., Petrelli, L., Caputo, I., Montemurro, C., Ruggieri, P., De Caro, R., and Stecco, C. (2023). A New Player in the Mechanobiology of Deep Fascia: Yes-Associated Protein (YAP). Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015389"},{"key":"ref_57","first-page":"322","article-title":"Efficacy of electroacupunture at Zusanli (ST36) on jumping-injured muscle based on transcriptome sequencing and genes analysis","volume":"43","author":"Han","year":"2023","journal-title":"J. Tradit. Chin. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/nn.4316","article-title":"YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells","volume":"19","author":"Poitelon","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8163052","DOI":"10.1155\/2020\/8163052","article-title":"Electroacupuncture Attenuates Inflammation after Ischemic Stroke by Inhibiting NF-\u03baB-Mediated Activation of Microglia","volume":"2020","author":"Liu","year":"2020","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Huang, J., You, X., Liu, W., Song, C., Lin, X., Zhang, X., Tao, J., and Chen, L. (2017). Electroacupuncture ameliorating post-stroke cognitive impairments via inhibition of peri-infarct astroglial and microglial\/macrophage P2 purinoceptors-mediated neuroinflammation and hyperplasia. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-1974-y"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"113431","DOI":"10.1016\/j.expneurol.2020.113431","article-title":"Astrocytic Yes-associated protein attenuates cerebral ischemia-induced brain injury by regulating signal transducer and activator of transcription 3 signaling","volume":"333","author":"Huang","year":"2020","journal-title":"Exp. Neurol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/96\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:26:13Z","timestamp":1759919173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/96"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,10]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["biom15010096"],"URL":"https:\/\/doi.org\/10.3390\/biom15010096","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,10]]}}}