Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective

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's 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.