Targeting DNA Damage and Repair Pathways in Cerebral Ischemic Stroke: From Bench to Bedside

Translational Stroke Research (2026) 17:11 https://doi.org/10.1007/s12975-025-01394-6 REVIEW Targeting DNA Damage and Repair Pathways in Cerebral Ischemic Stroke: From Bench to Bedside Zixian Xie1 · Yumin Luo1,2 · Ziping Han1 Received: 27 June 2025 / Revised: 4 October 2025 / Accepted: 8 October 2025 / Published online: 5 January 2026 © The Author(s) 2026 Abstract Despite advances in reperfusion therapies following cerebral ischemic stroke, effective treatment options remain limited, and achieving optimal outcomes post-revascularization continues to be a significant challenge. Increasing evidences have highlighted the crucial role of DNA damage and its associated downstream inflammatory and apoptotic pathways in the pathophysiology of stroke (collectively known as the DNA damage response, DDR). Enhancing DNA repair has emerged as a promising therapeutic approach to mitigate neural injury and promote function recovery after stroke. This review summarizes recent strategies aimed at neuroprotection through the modulation of DNA damage and repair pathways, focusing on both clinical patients with ischemic stroke and experimental stroke models. Additionally, we explore potential future directions. Keywords Ischemic stroke · Ischemia–reperfusion injury · DNA damage response · DNA repair enzymes · Mitochondrial DNA Introduction of Cerebral Ischemia/ Reperfusion Injury and DNA Damage Response Stroke is the second leading cause of global mortality and a principal contributor to disability[1], with ischemic stroke Communicated by Khalid A. Hanafy. Zixian Xie is the first author. Yumin Luo and Ziping Han are co-corresponding authors. Yumin Luo Ziping Han Zixian Xie 1 Institute of Cerebrovascular Diseases Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China 2 Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China comprising over 80% of all stroke cases of all stroke cases, predominantly resulting from arterial occlusion that induces cerebral circulation disorders[1, 2]. The two main therapeutic interventions for acute stroke are intravenous thrombolysis and endovascular thrombectomy; however, both are constrained by a narrow therapeutic window [3, 4], and are beneficial to less than 10% of patients with acute ischemic stroke (AIS) [5]. Even with successful revascularization, secondary injuries such as cerebral edema, intracranial hemorrhagic transformation, and other forms of ischemia–reperfusion injury may arise. Ischemia/reperfusion (I/R) injury triggers a cascade of pathophysiological activities including energy depletion, excitatory-amino-acid excitotoxicity, calcium overload and mitochondrial dysfunciton, exacerbating oxidative stress and leading to cell death through DNA damage, lipid peroxidation, and alterations in the structure of proteins [6–8]. To date, few neuroprotective agents have been successfully applied in the treatment of cerebral ischemia following revascularization [9]. Therefore, identifying potential effective cerebral cytoprotection therapy, when combined with recanalization to mitigate reperfusion injury, extend the therapeutic window and improve prognosis, is a critical focus in the treatment of acute stroke [10, 11]. DNA damage is an early event in acute brain injury including stroke, epilepsy and trauma, persisting into chronic 13 11 Page 2 of 25 phase [12]. Brain tissue is highly sensitive to hypoxia and ischemia, with DNA being particularly vulnerable. Following I/R injury, cerebral cell populations, particularly neurons, are exposed to a significant amount of reactive oxygen species (ROS) and other free radicals that directly leads to damage of various cellular structures, including nuclear and mitochondrial DNA [13]. In response to DNA damage, the organism initiates a comprehensive cascade of responses, ranging from detection, signal transduction, to the repair process. Additionally, inflammatory cytokines are induced and various pro-apoptotic signaling pathways are triggered, leading to cell death, and a series of irreversible damages such as cerebral edema and necrosis. The detrimental aspects of these responses are more accentuated under pathological conditions than physiological ones. This integrated set of reactions is collectively known as the DNA Damage Response (DDR) [14]. The core part of DDR is DNA damage repair [14]. Although DNA repair mechanisms will be activated soon after the onset of ischemic stroke [15], their efficiency is inherently limited, as neurons are post-mitotic cells with minimal DNA replication capacity. Their maintenance of genomic integrity relies on finite DNA repair mechanisms, which tend to deteriorate in the elderly. Alleviating DNA damage is essential for preserving genetic stability after ischemia/reperfusion (I/R) injury [16]. Moreover, DNA repair may promote the restoration of the nervous system, including synaptic remodeling, neurovascular regeneration, and myelin repair [17]. This article focuses on any drug or novel molecule targeting DNA damage response, or DNA damage repair pathways, aiming to cerebral cytoprotection against ischemia/reperfusion injury. DNA damage repair pathways hold promise as adjunctive therapies following revascularization treatments, reducing reperfusion injury and maximizing patient benefit. From Pathophysiology to Modulating Excessive Nucleic DNA Damage Response in Ischemic Stroke Nucleic DNA Damage After Acute Ischemic Stroke Oxidative DNA damage in neurons following cerebral I/R is directly initiated by ROS and reactive nitrogen species (RNS). Various sources such as mitochondrial respiratory chain, cytosolic xanthine oxidase, and microsomal Cyt P450 oxidoreductase generate ROS, with mitochondria being the main contributor due to their central role in cellular oxidative phosphorylation. ROS, particularly highly reactive species like hydroxyl radical (·OH) and peroxynitrite (ONOO−), damage DNA by modifying bases with double 13 Translational Stroke Research (2026) 17:11 bonds or removing hydrogen atoms. They also direct damage the ribose and phosphate-backbone, as well as other cellular structure [18, 19]. Concurrently, excessive activation of N-methyl-D-aspartate (NMDA) receptors and abnormal extracellular glutamate uptake exacerbate calcium overload, triggering the release of μ-calpain I, nNOS, mitochondrial cytochrome c, endonuclease G, apoptosis-inducing factor and DNase II. These DNA-breaking enzymes translocate to the nucleus of neuron and cause severe damage [20]. (Fig. 1). DNA damage causes a series of adverse consequences and may form vicious circles like chromosomal translocations or gross rearrangements, threaten the homeostasis [21]. In response, a complex network of abundant pathways can be activated to cope with this threat, generally defined as “DNA damage response” (DDR) [22]. In the steady state, (...truncated)