{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:31Z","timestamp":1787028571642,"version":"build-2736575974"},"reference-count":92,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cTor Vergata\u201d University of Rome","award":["UBP_GioiaM_CAMA-Gioia RSA TIPO B"],"award-info":[{"award-number":["UBP_GioiaM_CAMA-Gioia RSA TIPO B"]}]},{"name":"\u201cTor Vergata\u201d University of Rome","award":["6992022PFFPBL"],"award-info":[{"award-number":["6992022PFFPBL"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["UBP_GioiaM_CAMA-Gioia RSA TIPO B"],"award-info":[{"award-number":["UBP_GioiaM_CAMA-Gioia RSA TIPO B"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["6992022PFFPBL"],"award-info":[{"award-number":["6992022PFFPBL"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin\u2014a well-characterized TRPV1 agonist\u2014chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src\u2013acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes<\/jats:p>","DOI":"10.3390\/ijms26188816","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T14:14:55Z","timestamp":1757513695000},"page":"8816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A \u2018Spicy\u2019 Mechanotransduction Switch: Capsaicin-Activated TRPV1 Receptor Modulates Osteosarcoma Cell Behavior and Drug Sensitivity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9729-1886","authenticated-orcid":false,"given":"Arianna","family":"Buglione","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Becerril Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Sciences, Roma Tre University, 00154 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0294-5642","authenticated-orcid":false,"given":"Simone","family":"Dogali","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3939-4752","authenticated-orcid":false,"given":"Giulia","family":"Alloisio","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Department of Sciences, Roma Tre University, 00154 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1119-2303","authenticated-orcid":false,"given":"Chiara","family":"Ciaccio","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Luce","sequence":"additional","affiliation":[{"name":"Institute of Structure Matter del Consiglio Nazionale delle Ricerche ISM-CNR, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Marini","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3928-0276","authenticated-orcid":false,"given":"Luisa","family":"Campagnolo","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-3478","authenticated-orcid":false,"given":"Antonio","family":"Cricenti","sequence":"additional","affiliation":[{"name":"Institute of Structure Matter del Consiglio Nazionale delle Ricerche ISM-CNR, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0352-3547","authenticated-orcid":false,"given":"Magda","family":"Gioia","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chen, M.B., Javanmardi, Y., Shahreza, S., Serwinski, B., Aref, A., Djordjevic, B., and Moeendarbary, E. 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