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Transl. Med."],"published-print":{"date-parts":[[2025,12,17]]},"abstract":"<jats:p>\n                    Tyrosine kinase inhibitors (TKIs) have improved cancer outcomes but are limited by cardiovascular toxicity, most notably hypertension and heart failure. The underlying mechanisms remain poorly understood, hindering the development of protective strategies. Here, we investigated the role of endothelial mechanotransduction in mediating vascular and cardiac injury caused by the vascular endothelial growth factor receptor\u2013targeting TKI sunitinib. Using patient-specific induced pluripotent stem cell\u2013derived endothelial cells (iPSC-ECs) and a mouse model of TKI-induced hypertension, we identified down-regulation of\n                    <jats:italic toggle=\"yes\">piezo-type mechanosensitive ion channel component 1<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">PIEZO1<\/jats:italic>\n                    ), a mechanically activated ion channel, as a driver of endothelial dysfunction. Restoring\n                    <jats:italic toggle=\"yes\">PIEZO1<\/jats:italic>\n                    expression, either pharmacologically with Yoda1, a selective agonist, or through inducible overexpression in iPSC-ECs, reversed sunitinib-induced endothelial dysfunction and mitigated its hypertensive effects, providing both mechanistic and genetic validation of PIEZO1\u2019s protective role against vascular toxicity. In mice, cotreatment with sunitinib and Yoda1 prevented the long-term cardiac dysfunction observed after sunitinib exposure and normalized elevations in circulating cardiac stress biomarkers. Single-nucleus multiomic profiling of mouse hearts revealed that sunitinib exposure activated chromatin remodeling and fibrogenic programs, which were reversed with PIEZO1 activation. Human engineered cardiac organoids further demonstrated that sunitinib impaired cardiomyocyte function only in the presence of endothelial cells, confirming a role for disrupted endothelial-cardiomyocyte cross-talk in TKI cardiotoxicity. Together, these findings identify endothelial PIEZO1 as a mediator of TKI-induced hypertension and cardiac dysfunction and highlight PIEZO1 activation as a potential therapeutic strategy for protecting cardiovascular health during cancer therapy.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adv9403","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T19:00:39Z","timestamp":1765998039000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6044-4576","authenticated-orcid":true,"given":"Amit","family":"Manhas","sequence":"first","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, 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94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-8307","authenticated-orcid":true,"given":"David","family":"Wu","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipti","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Baszucki Family Vascular Surgery Biobank, Stanford University School of Medicine, Stanford, CA 94305, 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