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.
Newswise — 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 on March 8, 2024, in , 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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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).
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