2. Academic Validation
  3. A mitochondria-targeted idebenone derivative W1a mitigates cerebral ischemia-reperfusion injury by preserving mitochondrial integrity and suppressing neuroinflammation

A mitochondria-targeted idebenone derivative W1a mitigates cerebral ischemia-reperfusion injury by preserving mitochondrial integrity and suppressing neuroinflammation

  • Bioorg Chem. 2026 Jan:168:109356. doi: 10.1016/j.bioorg.2025.109356.
Mei Li 1,  Deyuan Kong 2,  Qingguo Ren 3,  Zhuopeng Li 3,  Zheyi Wang 1,  Zetai Bai 1,  Liying Meng 2,  Xuemeng Liu 2,  Zhongjun Yang 4,  Guanzhao Wu 5
Affiliations

Affiliations

  • 1 Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong 266035, China; Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China.
  • 2 Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong 266035, China; Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China.
  • 3 Department of Radiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China.
  • 4 Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China. Electronic address: yzhj@sdu.edu.cn.
  • 5 Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong 266035, China; Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China. Electronic address: guanzhao.wu@email.sdu.edu.cn.
PMID: 41370879 DOI: 10.1016/j.bioorg.2025.109356
Abstract

Cerebral ischemia-reperfusion injury (CIRI) represents a critical barrier to effective stroke treatment, characterized by mitochondrial dysfunction and neuroinflammatory cascades. Although idebenone (IDE), a CoQ10 analog with potent antioxidant properties, has shown therapeutic potential, its poor mitochondrial accumulation and pharmacokinetic limitations have hindered clinical efficacy. To overcome these challenges, we synthesized W1a, a novel IDE derivative conjugated to the mitochondria-targeting peptide SS-20, designed to enhance mitochondrial localization and pharmacodynamic activity. We demonstrated that W1a significantly ameliorated glutamate-induced oxidative injury in HT22 hippocampal neurons by preserving mitochondrial membrane potential (MMP), enhancing adenosine triphosphate (ATP) production, reducing Reactive Oxygen Species (ROS) accumulation, and maintaining mitochondrial morphology. In vivo, W1a conferred robust neuroprotection in a murine model of transient middle cerebral artery occlusion (tMCAO), as evidenced by reduced infarct volume, improved survival rates, and enhanced neurological recovery. Mechanistically, transcriptomic and biochemical analyses revealed that W1a restored mitochondrial gene expression, elevated NAD+/NADH and ATP levels, suppressed ROS overproduction, and downregulated pro-inflammatory signaling pathways. Moreover, W1a inhibited microglial and astrocytic activation, further supporting its anti-inflammatory efficacy. Collectively, our findings establish W1a as a potent neuroprotective agent that targets mitochondrial dysfunction and neuroinflammation drivers of CIRI pathology, offering a promising therapeutic strategy for ischemic stroke.

Keywords

Cerebral ischemia-reperfusion injury; Idebenone derivative; Mitochondria-targeted peptides; Mitochondrial dysfunction; Neuroprotection.

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