SignificanceNonapoptotic cell death-induced tissue damage has been implicated in a variety of diseases, including neurodegenerative disorder, inflammation, and stroke. In this study, we demonstrate that ferroptosis, a newly defined iron-dependent cell death, mediates both chemotherapy- and ischemia/reperfusion-induced cardiomyopathy. RNA-sequencing analysis revealed up-regulation of heme oxygenase 1 by doxorubicin as a major mechanism of ferroptotic cardiomyopathy. As a result, heme oxygenase 1 degrades heme and releases free iron in cardiomyocytes, which in turn leads to generation of oxidized lipids in the mitochondria membrane. Most importantly, both iron chelation therapy and pharmacologically blocking ferroptosis could significantly alleviate cardiomyopathy in mice. These findings suggest targeting ferroptosis as a strategy for treating deadly heart disease.

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SummaryEpigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling. However, the underlying regulatory mechanism remains to be elucidated. Here we identified a heart-enriched long non-coding (lnc)RNA, named Cardiac Hypertrophy Associated Epigenetic Regulator (Chaer), necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with Polycomb Repressor Complex 2 (PRC2) catalytic subunit through a 66-mer motif, interferes with its targeting to genomic locus, and subsequently inhibits histone H3 lysine 27 methylation at hypertrophic genes. This interaction is transiently induced upon hormone or stress stimulation in an mTORC1 dependent manner, and is prerequisite for epigenetic reprogramming and induction of hypertrophic genes. Inhibition of Chaer in intact heart before, but not after, the onset of pressure overload significantly attenuates cardiac hypertrophy and dysfunction. Therefore, our study reveals that stress-induced pathological gene activation in heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.