Stroke is the second leading cause of death (11.6%) worldwide [1]. Since the brain is the most sensitive organ in the human body to ischemia and hypoxia, acute ischemic stroke (AIS) poses a significant threat to human health [2,3]. Administration of recombinant tissue plasminogen activator (RTPA) or mechanical/endovascular thrombectomy is an early treatment option for AIS. However, studies have found that after patients undergo thrombolytic therapy within the therapeutic window, restoration of the blood supply to the brain not only fails to protect the brain but also causes serious brain damage, a phenomenon called CIRI. CIRI can damage cerebral microvascular endothelial cells and the blood-brain barrier, causing nerve-cell infiltration and brain edema [4], leading to the necrosis and apoptosis of nerve cells in the penumbra of the brain [5].

After CIRI, the aerobic metabolism of glucose in brain cells is weakened, the synthesis of adenosine-triphosphate is reduced, and ROS are abundantly generated [6], resulting in a large release of excitatory amino acids (EAAs) [7], calcium overload [8] and neuroinflammation [9], ultimately leading to increased inflammation and brain damage.

The accumulation of ROS causes oxidative stress, which in turn causes biomolecular damages, such as protein oxidation, lipid peroxidation, and oxidative DNA damage. The brain is an extremely sensitive organ to oxidative stress [10], which is one of the major causative factors of CIRI. Numerous studies have found that intracellular ROS level is increased during CIRI [[11], [12], [13]]. Furthermore, the oxidative DNA damage caused by ROS accumulation induces the DDR [14]. Severe DDR causes apoptosis [15,16].

Studies have found that many antioxidants show therapeutic potential in CIRI. Natural antioxidants, such as uric acid, glutathione, and Trolox have shown neuroprotective effects in studies in animals with focal cerebral ischemia [17]. Wang Han min et al. have found that mangiferin can inhibit the oxidative stress and inflammatory response caused by CIRI [18]. It has also been reported that trilobatin can suppress the oxidative stress in the brain of rats subjected to transient middle cerebral artery occlusion (tMCAO) and improve the CIRI by activating the Nrf2/Keap-1 signaling pathway that upregulate antioxidant enzymes [13].

DhHP-3 (Suppl. Figure 1) is a peroxidase mimetic with high peroxidase activity. It has high stability and exhibits high activity even in the presence of high sodium/calcium chloride, or in an alcohol solvent or high-phosphate buffer [19]. In vivo experiments have found that DhHP-3 can improve the oxidative damage of H2O2 and prolong lifespan in C. elegans. In our previous study we found that DhHP-6 could alleviate CIRI [20]. DhHP-3 had better plasma stability than DhHP-6 (Suppl. Fig. 2, Fig. 3). Therefore, we believe that DhHP-3 may have better potential for mitigating CIRI.