image: Schematic hypothesis. Ischemic stroke causes iron accumulation, disrupting the redox balance, which in turn leads to two outcomes. One of the outcomes is the increased cell susceptibility to ferroptosis, accompanied by the accumulation of lipid reactive oxygen species (ROS). Additionally, the disrupted redox balance induces the phosphorylation of RIPK1, amplifying susceptibility to necroptosis.
Credit: Genes & Diseases
A pivotal study has uncovered that iron orchestrates the activation of two damaging cell death pathways—ferroptosis and necroptosis—early in ischemic stroke recovery, exacerbating brain injury. This discovery sheds light on how iron disruption fuels neurological damage, positioning iron regulation as a promising therapeutic target to protect the brain during the critical reperfusion phase.
Ischemic stroke continues to rank among the top causes of death and long-term disability globally. While advances in acute treatments like clot retrieval and thrombolysis have improved outcomes, the challenge of managing reperfusion injury—a phase when restored blood flow can ironically harm brain tissue—persists. Key contributors to this damage are programmed cell death pathways, including ferroptosis and necroptosis. Yet, the intricate timing and interaction between these mechanisms remain poorly understood, leaving gaps in therapeutic strategies that urgently need addressing.
A team from Sichuan University, publishing their findings (DOI: 10.1016/j.gendis.2024.101262) on March 8, 2024, in Genes & Diseases, tackled this complex issue. Using RNA sequencing and protein analysis in ischemic mouse models, the researchers demonstrated that ferroptosis and necroptosis are triggered within hours of reperfusion, while apoptosis occurs later. They found that iron plays a central role in amplifying both early pathways by destabilizing redox balance, which accelerates oxidative damage and worsens neurological outcomes.
This groundbreaking research highlights the dynamic interplay between ferroptosis and necroptosis, revealing iron as a linchpin in their activation. The study also found that ferroptosis inhibitors like Liproxstatin-1 not only halt ferroptosis but also reduce necroptosis, and necroptosis inhibitors such as Necrostatin-1 show reciprocal effects. Iron chelation therapy with deferoxamine emerged as a particularly effective approach, mitigating both pathways by addressing the root cause—iron overload. These findings emphasize the need for early intervention and a multi-target therapeutic approach to minimize stroke-related damage.
Dr. Peng Lei, the study's lead author, remarked, “Our findings unravel the intricate relationship between ferroptosis and necroptosis in stroke recovery. Iron stands out as a crucial driver of these processes, offering a highly actionable target for novel therapies. This dual-pathway approach could significantly improve outcomes for ischemic stroke patients.”
Looking ahead, this research paves the way for the development of combination therapies targeting multiple cell death pathways to alleviate reperfusion injury. Iron chelation strategies, in particular, could redefine stroke management and recovery, while also providing a foundation for precision medicine in treating stroke and other neurodegenerative disorders.
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References
DOI
Original Source URL
https://doi.org/10.1016/j.gendis.2024.101262
Funding information
This work was supported by the National Key Research and Development Program of China (No. 2021YFC2500100), 1.3.5 Project for Disciplines of Excellence of West China Hospital of Sichuan University (No. ZYYC23016), the Key Research Projects of Sichuan Province, China (No. 24SYSX0093), Major Science & Technology Program of Sichuan Province, China (No. 2022ZDZX0021), the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (China) (No. Z2023LC005), the Natural Science Foundation of Sichuan Province, China (No. 2022NSFSC1509), and the Fundamental Research Funds for the Central Universities (China) (No. 2023SCU12074).
About Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases.
Journal
Genes & Diseases
Subject of Research
Not applicable
Article Title
Iron promotes both ferroptosis and necroptosis in the early stage of reperfusion in ischemic stroke
Article Publication Date
8-Mar-2024
COI Statement
The authors declare that they have no competing interests.