Ferroptosis as a target for protection against cardiomyopathy

Abstract

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.

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…As one of the important RCDs regulating homeostasis of organisms, ferroptosis plays an intricate role in human health. The onset of some diseases is considered to be related to ferroptosis . Therefore, improving the specificity and controlling the dosage of ferroptosis inducers are essential for reducing adverse effect on healthy tissues.…”

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

“…Ferrostatin‐1‐sensitive cell death can also be induced in cell models of Huntington's disease, periventricular leukomalacia, and Sertoli cell death induced by combined oxygen and glucose deprivation . Ischemia‐reperfusion injury (IRI), occurring when a tissue is deprived of blood or oxygen for an extended period and then reperfused (e.g., after stroke), can trigger ferroptosis in the small intestine, testes, liver, heart, kidney, and brain that can be prevented by known ferroptosis inhibitors or genetic inhibition of ACSL4 expression . Inhibition of ferroptosis can also improve brain cell survival and neurological outcomes after hemorrhagic stroke and traumatic brain injury .…”

A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators

“…2c). Thus, intrinsic antioxidant activity is likely to explain the ability of these compounds to inhibit 9 ferroptosis.…”

“…Small molecules that can induce ferroptosis may be useful to selectively target certain cancer cells 4,6,7 . By contrast, small molecules that can inhibit this process may be useful to prevent cell death in diverse pathological contexts 8,9 . Greater insights into the basic mechanisms of ferroptosis, along with modulators of this process suitable for clinical use, are urgently needed 10 .…”