{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:25:32Z","timestamp":1787037932935,"version":"build-2736575974"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Soft tissue fibrosis and chronic pain involve a cycle linking extracellular matrix (ECM) stiffening, inflammation, and neural sensitization. This review develops a multiscale framework that spans from molecular mechanisms to organ-level physiology and focuses on the directly mechanosensitive Piezo1\/2 channels and the mechano-responsive TRPV4 channel, drawing on their distinct molecular architectures to ground divergent gating properties. We examine how these channels convert membrane tension and integrin-mediated traction into Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and other ionic signals that, together with Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -independent pathways engage YAP\/TAZ, NF-\u03baB, and TGF-\u03b2 pathways, thereby reshaping transcriptional programs. We then conceptualize healthy ECM as a \u201cspatial filter,\u201d noting that viscoelasticity and non-affine fiber rearrangements buffer superficial loads, whereas fibrotic cross-linking erodes this protection, chronically exposing fibroblasts and sensory endings to elevated mechanical and inflammatory cues. This may drive pathological \u201cstiffness\u2013inflammation\u2013fibrosis\/pain\u201d loops. Finally, we propose a mechanical therapeutic window in which mechanical interventions, parameterized by channel modulation and\/or viscoelastic biomaterials, reset the local environment toward a near-physiological state. Within this Goldilocks zone, reparative and inflammation-resolving pathways can be preferentially engaged while minimizing damage and pain amplification. This integrated perspective offers a conceptual framework for understanding fibrosis-associated disorders and chronic soft-tissue pain, and may inform therapies targeting Piezo\/TRPV4 signaling and ECM viscoelasticity.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1869360","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:40:57Z","timestamp":1787035257000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Soft tissue mechanosensing and remodeling: the core regulatory role of Piezo\/TRPV4 ion channels"],"prefix":"10.3389","volume":"14","author":[{"given":"Xuanqiang","family":"Fan","sequence":"first","affiliation":[{"name":"The Third Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]},{"name":"School of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwei","family":"Shi","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]},{"name":"School of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]},{"name":"School of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]},{"name":"School of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]},{"name":"School of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3053","DOI":"10.3390\/cells10113053","article-title":"TRPV4 mechanotransduction in fibrosis","volume":"10","author":"Adapala","year":"2021","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.actbio.2016.03.034","article-title":"Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen","volume":"37","author":"Babaei","year":"2016","journal-title":"Acta Biomater."},{"key":"B4","doi-asserted-by":"publisher","first-page":"6295","DOI":"10.1021\/bi200770q","article-title":"The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4","volume":"50","author":"Bae","year":"2011","journal-title":"Biochemistry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"051005","DOI":"10.1115\/1.3049527","article-title":"Magnitude and duration of stretch modulate fibroblast remodeling","volume":"131","author":"Balestrini","year":"2009","journal-title":"J. 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