TET3 is a regulator and can be targeted for the intervention of myocardial fibrosis.

Cardiac fibrosis as an integral part of the wound healing process on the one hand safeguards myocardial homeostasis but on the other hand contributes to adverse cardiac remodeling and loss of heart function eventually leading to heart failure (HF). Resident cardiac fibroblasts are the principal source of myofibroblasts that produce extracellular matrix proteins to mediate cardiac fibrosis. We investigated the involvement of ten-and-eleven translocator 3 (TET3) in this process focusing on the regulatory mechanism and translational potential. We report that TET3 depletion in cultured cardiac fibroblasts blocked transition to myofibroblasts in response to different pro-fibrogenic stimuli. Consistently, deletion of TET3 from quiescent or activated fibroblast (myofibroblast) attenuated cardiac fibrosis and rescued heart function in models of cardiac injury. Importantly, a small-molecule TET3-specific degrader Bobcat339 displayed therapeutic potential by mitigating cardiac fibrosis and normalizing heart function when administered post-surgery. Integrated transcriptomic analysis (RNA-seq and CUT&Tag-seq) identified the mechanosensor Piezo2 as a downstream target for TET3. Piezo2 deletion or inhibition dampened fibroblast activation in vitro and ameliorated cardiac fibrosis in vivo. Mechanistically, Piezo2 promoted fibroblast activation by modulating the activities of mechanosensitive transcription factors. Finally, relevance of the TET3-Piezo2 axis was verified in heart specimens collected from HF patients. Our data demonstrate that TET3 is a pivotal regulator of cardiac fibrosis and can be potentially targeted for the intervention of heart failure. Overall design: Mouse primary cardiac fibroblasts were induced to undergo Tet3 knockout by transfection with Cre recombinase virus, followed by TGF-ß treatment.