Ferroptosis as a target for protection against cardiomyopathy

TLDR

Nonapoptotic cell death–induced tissue damage contributes to neurodegenerative disorders, inflammation, and stroke. The study demonstrates that ferroptosis mediates chemotherapy‑ and ischemia/reperfusion‑induced cardiomyopathy. Heme oxygenase‑1 degrades heme, releases free iron, and triggers oxidized lipid production in cardiomyocyte mitochondria. RNA‑seq identified HO‑1 up‑regulation by doxorubicin as a key driver, and both iron chelation and ferroptosis inhibition markedly reduced cardiomyopathy in mice, supporting ferroptosis as a therapeutic target.

Abstract

Significance Nonapoptotic 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.