New insights in ferroptosis: Potential therapeutic targets for the treatment of ischemic stroke

Abstract

Stroke is a common disease in clinical practice, which seriously endangers people's physical and mental health. The neurovascular unit (NVU) plays a key role in the occurrence and development of ischemic stroke. Different from other classical types of cell death such as apoptosis, necrosis, autophagy, and pyroptosis, ferroptosis is an iron-dependent lipid peroxidation-driven new form of cell death. Interestingly, the function of NVU and stroke development can be regulated by activating or inhibiting ferroptosis. This review systematically describes the NVU in ischemic stroke, provides a comprehensive overview of the regulatory mechanisms and key regulators of ferroptosis, and uncovers the role of ferroptosis in the NVU and the progression of ischemic stroke. We further discuss the latest progress in the intervention of ferroptosis as a therapeutic target for ischemic stroke and summarize the research progress and regulatory mechanism of ferroptosis inhibitors on stroke. In conclusion, ferroptosis, as a new form of cell death, plays a key role in ischemic stroke and is expected to become a new therapeutic target for this disease.

Keywords: ferroptosis; inhibitors; neurovascular unit (NVU); stroke; therapeutic target.

FIGURE 1

Schematic diagram of the pathological mechanism of ischemic stroke. Ischemic stroke triggers cascades of complex events that cause oxidative stress and excitotoxicity due to the accumulation of ROS and calcium (Ca²⁺), blood-brain-barrier (BBB) breakdown and activated inflammatory responses. Excessive ROS and Ca²⁺ lead to mitochondrial dysfunction and activation of apoptotic factors, ultimately leading to apoptosis and necrotic cell death.

FIGURE 2

Regulatory mechanisms of ferroptosis. The primary metabolism involved in ferroptosis can be roughly divided into three categories: iron metabolism, System Xc⁻/GSH/GPX4 pathway, and lipid peroxidation. Besides, the FSP1-CoQ₁₀-NAD(P)H pathway, which exists as an independent parallel system with GPX4 and GSH, inhibits phospholipid peroxidation and ferroptosis.

FIGURE 3

The mechanisms of ferroptosis in ischemic stroke. Following ischemic stroke, the BBB is disrupted, which allows Fe³⁺ in the blood to be released into cells through TF and TFR1, then stored in the endosome, where Fe³⁺ is converted into Fe²⁺ and transported to the cytoplasm by DMT1 with the cooperation of STEAP3. The excess Fe²⁺ generates ROS and participates in the synthesis of PUFA lipid peroxides (L-OOH), which can induce ferroptosis; System Xc⁻ is simultaneously impaired, which inhibits cystine-glutamate exchange and reduces the generation of GSH and GPX4, thereby inhibiting lipid alcohol (L-OH) production, ultimately leading to ferroptosis. Additionally, the Nrf2 pathway can inhibit ferroptosis and alleviate ischemic stroke injury by inducing GSH, SLC7A11, and GPX4 transcription.

FIGURE 4

Possible molecular mechanisms of ferroptosis and potential therapeutic targets in ischemic stroke. The decrease of GSH, GPX4, tau protein, and the increase of lipoxygenase (LOX), and BBB permeability, can lead to the occurrence of ferroptosis in ischemic stroke. Iron chelators like deferoxamine (DFO), ciclopirox (CPX) and 2,2-bipyridyl (2,2-BP) can inhibit ferroptosis; Lipoxygenase inhibitors like Baicalein, Vitamin E, ML351 and Zileuton can suppress LOXs activity to rescue cells from ferroptosis; Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) inhibit radical-trapping antioxidants which activate LOXs to prevent ferroptosis in cells.