Ferroptosis in Ischemic Stroke and Related Traditional Chinese Medicines

Abstract

Stroke is a severe neurological disorder resulting from the rupture or blockage of blood vessels, leading to significant mortality and disability worldwide. Among the different types of stroke, ischemic stroke (IS) is the most prevalent, accounting for 70-80% of cases. Cell death following IS occurs through various mechanisms, including apoptosis, necrosis, and ferroptosis. Ferroptosis, a recently identified form of regulated cell death characterized by iron overload and lipid peroxidation, was first described by Dixon in 2012. Currently, the only approved pharmacological treatment for IS is recombinant tissue plasminogen activator (rt-PA), which is limited by a narrow therapeutic window and often results in suboptimal outcomes. Recent research has identified several traditional Chinese medicines (TCMs) that can inhibit ferroptosis, thereby mitigating the damage caused by IS. This review provides an overview of stroke, the role of ferroptosis in IS, and the potential of certain TCMs to inhibit ferroptosis and contribute to stroke treatment.

Keywords: ferroptosis; natural products; stroke; traditional Chinese medicine.

Figure 2

The core mechanisms of ferroptosis. The system Xc⁻/GPX4 axis regulates ferroptosis by modulating cystine uptake, GSH synthesis, and reduction in lipid peroxides by GPX4. The FSP1/CoQ axis is parallel and independent system that synergizes with the GSH-GPX4 axis to in-hibit ferroptosis, and FSP1 reduces CoQ to CoQH₂, preventing the production of lipid peroxides and inhibiting ferroptosis. The GCH1/BH4/DHFR axis can protect against ferroptosis in a GPX4-independent manner, GCH1-BH4 axis controls the production of the endogenous antioxidant BH4, thereby regulating ferroptosis. TFR1 transports Fe³⁺ into the membrane, and in the endosomes, STEAP3 reduces Fe³⁺ to Fe²⁺, and Fe²⁺ enters the cytoplasm via SLC11A2/DMT1. When cerebral is-chemia stroke occurs, the ability of FPN to transport iron ions outward is reduced, which exacer-bates the deposition of iron, and Fe²⁺ participates in the Fenton reaction, which induces the accumu-lation of lipid peroxides, leading to ferroptosis. PUFA exacerbates lipid peroxidation in the presence of ACSL4, LPCAT3, and ALOX.

Figure 3

Structures of compounds that induce ferroptosis.

Figure 4

Structures of compounds that inhibit ferroptosis.

Figure 1

Partitioning and symptoms of ischemic stroke. Ischemic strokes are caused by the for-mation of blood clots in the blood vessels, which reduces blood flow and causes infarction in some areas. The infarcted area can be divided into the core area of the cerebral infarction and the ischemic penumbra around the core area. And ischemic strokes cause abnormal behavior, such as a sudden onset of imbalance, blurred or unclear vision, facial weakness or asymmetry, weakness of the arms or legs, difficulty in speech, and so on.