Myocardial Infarction: Targeting Ferroptosis

Myocardial infarction treatments primarily focus on restoring blood flow and mitigating immediate threat, but they often fail to address the irreversible cell damage caused during a heart attack. Understanding cell death mechanisms, particularly ferroptosis, offers a promising avenue for developing more comprehensive treatments. Here, miR331 and SIRT1 were identified as targets affecting ferroptosis in myocardial infarction.

Myocardial infarction (heart attack) is the leading cause of death worldwide,¹ affecting over 800,000 people annually in the U.S. alone.² During such an event, obstructed coronary arteries diminish oxygen supply to the heart, risking severe cardiac damage or death.

Current treatments for myocardial infarction include thrombolytic medications and surgical procedures, depending on the severity. Pacemakers can also been implanted after a heart attack to prevent life-threatening arrythmias. While effective in restoring blood flow and alleviating immediate threat, these treatments do not directly address the irreversible cell damage caused by a heart attack.

Cell death mechanisms, such as ferroptosis, play a crucial role in causing irreversible damage, leading to the loss of heart tissue. Targeting such mechanisms could offer a promising avenue for developing comprehensive and long-lasting therapeutics for this condition.

Ferroptosis is distinct for its iron-dependency and its role in lipid peroxidation, characterized by the accumulation of lipid peroxides and reactive oxygen species. This iron-driven process is critical in promoting harmful lipid peroxides, making it a unique form of programmed cell death.

During myocardial infarction, ferroptosis has a pivotal role. Iron overload results in cardiac dysfunction and amplifies oxidative harm to the myocardium.³ This process further aggravates cardiomyocyte death and tissue injury during ischemia-reperfusion,⁴ making the heart more susceptible to iron-triggered oxidative stress. Targeting ferroptosis could be a promising option to improve survival and prognosis for myocardial infarction patients.⁴

Causaly’s analysis unveiled around 200 targets affecting ferroptosis in myocardial infarction, around 70 of which have been reported in primary data. Filtering further by study type revealed around 50 targets studied in vivo. Targets were then selected based on the strength of evidence and those reported in 2023.

MicroRNA 331 (miR331) was among targets with the highest evidence score. A 2023 study revealed that the long non-coding RNA AC005332.7 binds to miR-331-3p to upregulate CCND2 expression, thereby inhibiting ferroptosis in oxygen and glucose-deprived AC16 human cardiomyocyte cells in vitro and in models of acute myocardial infarction in vivo.⁵ This suggests that miR-331-3p is a potential target for reducing heart cell damage through the suppression of ferroptosis. ⁵

SIRT1, which encodes for NAD+-dependent histone deacetylase, plays a multifaceted role in regulating endocrine functions and protection against oxidative stress. A 2023 showed that circular RNA FEACR stabilizes nicotinamide phosphoribosyltransferase, leading to the upregulation of SIRT1.⁶ This in turn activates FOXO1-FTH1 signaling axis to inhibit ferroptosis in cardiomyocytes during myocardial ischemia/reperfusion injury in vivo.⁶ This highlights SIRT1 as a key mediator in the FEACR-driven pathway and a potential therapeutic target for ferroptosis-related myocardial injury.

Current therapies for myocardial infarction often overlook irreversible cell injury associated with heart attacks. Recent 2023 research points to ferroptosis-related targets, such as miR331 and SIRT1, as promising therapeutic modalities for more effective treatments.