Ferroptosis: a potential target for the treatment of atherosclerosis

Abstract

Atherosclerosis (AS), the main contributor to acute cardiovascular events, such as myocardial infarction and ischemic stroke, is characterized by necrotic core formation and plaque instability induced by cell death. The mechanisms of cell death in AS have recently been identified and elucidated. Ferroptosis, a novel iron-dependent form of cell death, has been proven to participate in atherosclerotic progression by increasing endothelial reactive oxygen species (ROS) levels and lipid peroxidation. Furthermore, accumulated intracellular iron activates various signaling pathways or risk factors for AS, such as abnormal lipid metabolism, oxidative stress, and inflammation, which can eventually lead to the disordered function of macrophages, vascular smooth muscle cells, and vascular endothelial cells. However, the molecular pathways through which ferroptosis affects AS development and progression are not entirely understood. This review systematically summarizes the interactions between AS and ferroptosis and provides a feasible approach for inhibiting AS progression from the perspective of ferroptosis.

1. Introduction

Atherosclerosis (AS) is a chronic and progressive arterial disease primarily caused by interactions among vascular endothelial cell (EC) injury, lipid deposition, and the inflammatory response [1]. This disease is mainly associated with large- and medium-sized arteries, such as the coronary, carotid, and lower-extremity arteries [2]. AS is a prevalent cardiovascular disorder worldwide and is the primary contributor to adverse outcomes in individuals with cardiovascular and cerebrovascular conditions. AS is a chronic progressive disease that most frequently occurs in the elderly population. Although the incidence of AS has declined in some countries in recent decades, it remains the leading cause of death globally [3].

Lifestyle changes such as reducing carbohydrate and fat intake, engaging in regular physical activity, and avoiding smoking are essential components of a multifaceted approach to prevent AS progression [4]. However, lifestyle modifications are difficult to accomplish. Therefore, effective targets and safe therapeutic strategies are needed to reduce the incidence of AS [5].

Oxidative stress, characterized by an imbalance between the generation of reactive oxygen species (ROS) and the presence of antioxidants or free radical scavengers, plays a crucial role in AS [6]. A growing body of evidence suggests that ferroptosis is strongly associated with ROS generation, iron homeostasis, and lipid peroxidation induced by diverse physiological and pathological stressors in both humans and animal models [7–9]. Ferroptosis, which is associated with iron and lipid metabolism, plays a pathological role in AS by linking it to oxidative stress.