PIEZO1 gain-of-function mutation drives cardiomyopathy by disrupting myocardial lipid homeostasis besides iron overload

As a mechanosensitive channel, PIEZO1 translates mechanical stretching of cardiomyocytes into Ca²⁺ signaling, underpinning the Frank-Starling law. This mechanism contributes to compensatory responses in heart failure. However, the relationship between PIEZO1 mutations and the development of cardiomyopathy remains unclear. Acute heart failure complicated with severe myocardial iron deposition was identified in the 31-year-old male proband of PIEZO1^D669Y variant. However, PIEZO1 gain-of-function (GOF) mutation D674Y mice and cardiomyocyte-specific <i>Piezo1</i> overexpression disrupted cardiac function besides iron overload. Using single-cell RNA sequencing, we observed suppression of lipid metabolism pathways in cardiomyocytes with the PIEZO1 GOF mutation, with forkhead box O3 (FOXO3) as a key mediator in lipid metabolism pathways. Specifically, the PIEZO1 GOF mutation increased Ca²⁺ levels, leading to calcium- and calmodulin-dependent protein kinase II (CaMKII) activation and subsequent FOXO3 down-regulation. Together, we demonstrate that PIEZO1 GOF mutation contributes to cardiomyopathy by disrupting myocardial lipid metabolism. This study challenges the current clinical focus on iron-related mechanisms in cardiomyopathy and supports PIEZO1 as a potential candidate for future genetic screening for cardiomyopathy.