Protective Effect of Chinese Herbal Medicine on Cerebral Ischemia-Reperfusion Injury by Regulating Ferroptosis

Abstract

Ischemic stroke remains one of the leading causes of death and long-term disability worldwide. The current standard-of-care therapies-intravenous thrombolysis and mechanical thrombectomy-restore cerebral blood flow but may paradoxically evoke cerebral ischemia-reperfusion injury. Recent studies have revealed that ferroptosis, a form of regulated cell death dependent on iron, plays a pivotal role in cerebral ischaemia-reperfusion injury. Traditional Chinese herbal formulas and their bioactive components can modulate ferroptosis, thereby mitigating brain damage induced by ischemia-reperfusion. This article reviews the molecular mechanisms of ferroptosis and its pathophysiological roles in cerebral ischaemia-reperfusion. It focuses particularly on the key mechanisms underlying the therapeutic effects of Chinese herbal medicines in targeting ferroptosis. The aim is to provide a theoretical basis for developing novel therapeutics.

Keywords: Chinese herbal medicine; cerebral ischemia-reperfusion injury; ferroptosis; protective effect.

Figure 1

Mechanism of ferroptosis. Excessive iron uptake mediated by TfR1, coupled with impaired FPN1 function, collectively leads to an elevation of LIP., Upregulated NCOA4 expression induces ferritinophagy, further releasing Fe²⁺ and exacerbating LIP accumulation. Fe²⁺ within the LIP drives the Fenton reaction, generating abundant ROS that attack PL-OOH, triggering lipid peroxidation and ultimately inducing ferroptosis. Moreover, an imbalance in the antioxidant defense system is another critical driver of ferroptosis. Dysfunction of the System Xc⁻/GPX4 axis blocks Cys₂ uptake, suppresses GSH synthesis, and consequently deprives GPX4 of its essential electron donor required for reducing lipid hydroperoxides. As a result, GPX4 cannot reduce PUFA-PL-OOH, thereby promoting ferroptosis. Other antioxidant pathways also participate in the regulation of ferroptosis. FSP1 blocks lipid peroxidation by reducing CoQ10 to CoQH₂; as the rate-limiting enzyme in BH4 synthesis, GCH1 produces BH4, which scavenges lipid radicals and suppresses ferroptosis.,

Figure 2

Signaling pathway regulatory mechanism of ferroptosis. Multiple signaling pathways regulate Ferroptosis. On one hand, several pathways suppress ferroptosis through distinct mechanisms. AMPK pathway can inhibit PUFAs synthesis and activate the master antioxidant transcription factor Nrf2, upregulating the expression of genes such as GPX4 and SLC7A11 and enhancing cellular antioxidant capacity. Under conditions of elevated ROS, Keap1 is inactivated, leading to the release and nuclear translocation of Nrf2, where it initiates the transcription of a suite of antioxidant genes., Additionally, PI3K/AKT pathway stabilizes Nrf2 or directly upregulates SLC7A11 expression, thereby promoting the synthesis of GSH and GPX4 and inhibiting lipid peroxidation., Wnt/β-catenin pathway can also suppress ferroptosis by upregulating FPN or SLC7A11 expression., Furthermore, VSTM2L exerts anti-ferroptotic effects by inhibiting VDAC1. On the other hand, specific signaling pathways can also promote ferroptosis., cGAS–STING pathway, upon activation by cytosolic DNA, enhances ACSL4 activity to drive lipid peroxidation. Additionally, it can increase LIP through ferritinophagy, collectively accelerating ferroptosis., p53 plays a dual role: in a transcription-dependent mode, p53 suppresses SLC7A11 expression and activates the pro-ferroptotic enzyme ALOX15, thereby promoting ferroptosis; in a transcription-independent mode, p53 can reduce ROS production and thus inhibit lipid peroxidation. Within the MAPK family, ERK signaling promotes Nrf2 expression. Consequently, it suppresses ferroptosis, whereas JNK/p38 signaling upregulates TfR1, enhancing cellular iron uptake, expanding the LIP, and amplifying Fenton reactions to induce ferroptosis. In the JAK–STAT pathway, activated JAK1/2 phosphorylates STAT1, which then represses SLC7A11 transcription, blocking Cys₂ uptake and leading to GPX4 inactivation—thereby exerting a pro-ferroptotic effect. However, when IL-6 activates JAK2, the JAK2-STAT3 axis, it upregulates SLC7A11 and GPX4 expression, leading to an anti-ferroptotic effect., Hippo–YAP/TAZ pathway shows strong context dependence with cell density: at low cell density, dephosphorylated YAP/TAZ translocates into the nucleus and upregulates pro-ferroptotic genes such as ACSL4 and TfR1; in contrast, at high cell density, this pathway switches to suppress ferroptosis.

Figure 3

Mechanism of Ferroptosis in CIRI. Ischemia and hypoxia activate HIF-1α, which promotes TfR1-mediated iron uptake. Upon reperfusion, ferritinophagy and BBB disruption synergistically cause intracellular iron overload, providing an abundant substrate for the Fenton reaction and leading to ROS generation. Restoration of blood flow during reperfusion further induces massive ROS production through mitochondrial dysfunction, activation of XO and PLA2, and neutrophil infiltration., ROS then drives lipid peroxidation via enzymatic pathways, such as the oxidation of PUFAs by ALOX, and non-enzymatic mechanisms, such as the Fenton reaction. Concurrently, ATP depletion disrupts ionic homeostasis and suppresses System xc-mediated cystine uptake, thereby impairing GSH synthesis and reducing GPX4 activity. Consequently, lipid peroxides cannot be effectively cleared, culminating in ferroptosis.

Figure 4

Effect of Chinese herbal metabolite concentration on cell viability.