Research identifies iron as crucial driver of stroke-related cell death processes

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.

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."

Dr. Peng Lei, study's lead author

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.